Carbapenem compounds

ABSTRACT

Carbapenem compounds represented by the general formula [1] or pharmaceutically acceptable salts thereof: 
                         
wherein R 1  is C 1 -C 3  alkyl or hydroxylated C 1 -C 3  alkyl, R is hydrogen atom or a group which is hydrolyzed in vivo into a carboxy group, and G is a group represented by one of the formulae [G1], [G2], and [G3].

TECHNICAL FIELD

The present invention relates to a new carbapenem compound. In moredetail, the present invention relates to a carbapenem compound, whichcontains 7-oxo-1-azabicyclo[3.2.0]hept-2-ene, wherein a substitutedphenyl is directly substituted at position 3. Furthermore, the presentinvention relates to an antibacterial agent containing such a compoundas an active ingredient.

BACKGROUND ART

The carbapenem compounds which have been developed and commercializedare poor in absorbability from the digestive tract and therefore, theyare clinically used only in the form of injections, mainly intravenousinjections. However, in the clinical field, it is desirable to selectseveral administration routes from the viewpoint of circumstances orwishes of a patient, a therapeutic object, etc. Especially, oraladministration of an antibacterial agent is easy and convenient foradministration to a patient in comparison with injection. In view of thecare of a patient at home, oral administration of the antibacterialagent is more convenient and the clinical usability is extremely high.It has been strongly desired in the clinical field to develop acarbapenem compound which is rich in safety, is orally administrable andhas a potent antibacterial activity, especially against penicillinresistant Streptococcus pneumoniae (PRSP) or Haemophilus influenzae(which widely gain resistance to known β-lactam agents by mutation of apenicillin binding protein (PBP), such as β-lactamase non-producingampicillin resistant Haemophilus influenzae (BLNAR) which have beenrecently increasingly isolated and provide a clinical trouble.). Howevernone of such agents has been put on the market. Tricyclic carbapenemcompounds which have been studied and developed until now are disclosedfor example, in WO92/03437. These compounds have a characteristicstructure in a side chain having a ring which is fused via C—C bond andthey are modified to a prodrug thereof for increase of oralabsorbability, but their safety in the clinical test is not reported.Besides, there are several known 1β methylcarbapenem compounds (see WO92/03437, Japanese patent publication A 2-49783, Japanese patentpublication A 8-53453, WO 98/34936, WO 99/57121, Japanese patentpublication A 4-279588, Japanese patent publication A 2-223587, andAntimicrobial Agents and Chemotherapy, March 1999, p 460-464). All ofthem have a structural property having 1β-methyl group and a side chainvia sulfide bond which are said to contribute to an increase of chemicalstability and in vivo (biological) stability, and are modified to aprodrug of them for increase of oral absorbability. Especially, theclinical trial was carried out on compounds disclosed in Japanese patentpublication A 2-49783 and Japanese patent publication A 8-53453, but thesafety of them and so on have been not clear.

On the other hand, carbapenem compounds having an aryl ring via C—C bondas a side chain structure were known since 1980s (see U.S. Pat. Nos.4,543,257, 4,775,669, 5,258,509, WO 02/053566, Tetrahedron, 1983, Vol.39, p 2531-2549, Journal of Medicinal Chemistry, 1987, Vol. 30, p871-880, EP 538001, and EP 538016). For example, in U.S. Pat. No.4,543,257, carbapenam compounds directly substituted bypara-methoxyphenyl group at position 3 of7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a core structure of thecarbapenem, and various compounds are described, and in the Journal ofMedicinal Chemistry, Vol. 30, p 871-880 (1987), carbapenam compoundsdirectly substituted by para-methoxyphenyl group at position 3 of7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a basic nucleus of thecarbapenem and so on are described. Although there are many otherreports on these compounds, these reports are concerned only to studiesand developments on injections thereof, but not to studies for oralapplication thereof.

Recently, carbapenem derivatives having a benzene ring and so ondirectly bound by substituted carbamoyl group at position 3 of7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a core structure of thecarbapenem (for example, WO 02/053566), carbapenem derivatives having abenzene ring bound via spacer with substituted carbamoyl group atposition 3 of 7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a corestructure of the carbapenem (for example, WO 03/040146), and carbapenemderivatives having a substituted pyridine ring, etc. at position 3 of7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a core structure of thecarbapenem (for example, WO 03/089431) are suggested to be used for oralagents, but the carbapenem derivatives having such a substituent patternas the compound of the present invention are not known and that suchcompounds are not known as oral antibacterial agents.

DISCLOSURE OF INVENTION

The object of the present invention is to provide a carbapenem compoundwhich has a potent antibacterial activity against Gram positive bacteriaand Gram negative bacteria, especially penicillin resistantStreptococcus pneumoniae (PRSP) or Haemophilus influenzae (which obtainresistance to known β-lactam agents by mutation of a penicillin bindingprotein (PBP) such as β-lactamase non-producing ampicillin resistantHaemophilus influenzae (BLNAR), which have been recently increasinglyisolated and provide a clinical problem) and has excellent oralabsorbability.

The present inventors have intensively studied to find that thecarbapenem compound, wherein a substituted phenyl is directlysubstituted at position 3 of 7-oxo-1-azabicyclo[3.2.0]hept-2-ene whichis a core structure of the carbapenem compound, has a potentantibacterial activity against Gram positive bacteria and Gram negativebacteria, especially penicillin resistant Streptococcus pneumoniae(PRSP) or Haemophilus influenzae which obtain resistance to knownβ-lactam agents by mutation of a penicillin binding protein (PBP) suchas β-lactamase non-producing ampicillin resistant Haemophilus influenzae(BLNAR) which have been recently increasingly isolated and provide aclinical problem. Further, they have also found that a compound having agroup substituted onto the 2-carboxyl group, the said group beingcapable of regenerating a carboxyl group by hydrolyzing in the livingbody, shows a good absorbability from the digestive tract by oraladministration, and shows a potent antibacterial activity afterconverted into a 2-de-esterified compound in the living body, andfurther shows an excellent resistance to renal dehydropeptidase. Thusthe present invention finally has been accomplished.

Namely the summary of the present invention are as follows.

-   (1) A carbapenem compound or a pharmaceutically acceptable salt    thereof represented by the following formula [1]

wherein R¹ is C₁-C₃ alkyl group or C₁-C₃ alkyl group substituted byhydroxy group,

R is hydrogen atom or a group which reproduces carboxyl group byhydrolysis in vivo, and

G is a group represented by

the formula G1:

the formula G2:

wherein Y¹ is C₁-C₄ alkyl, C₂-C₄ alkoxy, —(CH₂)_(ma)—O—CH₃ (in which mais an integer of 1˜3), —O—(CH₂)_(ma)—O—(CH₂)_(mb)—CH₃ (in which ma isthe same as defined above, mb is an integer of 0˜3), trifluoromethoxy,halogen atom, cyano or —SO₂NR²R³ (in which R² and R³ are independentlyhydrogen atom, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, or optionally substituted heteroarylalkyl, or R²and R³ may be taken together with the nitrogen atom to form a 3 to 7membered hetero ring which may be substituted.),

or the formula G3:

wherein A is —(CH₂)_(r)—(in which r is an integer of 1˜3),—(CH₂)_(s)—O—(CH₂)_(t)—(in which s and t are independently is an integerof 0˜3), —O—(CH₂)_(r)—O—(CH₂)_(s)—(in which r and s are the same asdefined above), —(CH₂)_(s)—NR^(a)—(CH₂)_(t)—(in which, s and t are thesame as defined above, R^(a) is hydrogen atom, protective group of aminogroup or optionally substituted C₁-C₆ alkyl), R⁰ is hydrogen atom, theformula [2]:

wherein R^(2a) and R^(3a) are independently (i) hydrogen atom, (ii)optionally substituted C₁-C₆ alkyl, (iii) optionally substituted C₃-C₇cycloalkyl, (iv) optionally substituted aryl, (v) optionally substitutedheteroaryl, (vi) optionally substituted aralkyl, (vii) optionallysubstituted heteroarylalkyl, or (viii) an optionally substituted 3 to 7membered hetero ring, or R^(2a) and R^(3a) are taken together with thenitrogen atom to form a 3 to 7 membered hetero ring which may besubstituted, or

the formula [3]:

wherein m is an integer of 0 or 1, R^(3b) is hydrogen atom, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl, optionally substituted heteroarylalkyl,or an optionally substituted 3 to 7 membered hetero ring, and when m is1, R^(3b) may further mean a group which reproduces carboxyl group byhydrolysis in vivo, provided that when t is 0 and m is 1, R^(3b) isother group than hydrogen atom, and Y² is C₁-C₄ alkyl, C₁-C₄ alkoxy,halogen atom, cyano or —NR⁴R⁵ (in which R⁴ and R⁵ are independently

(i) hydrogen atom, (ii) a protective group of amino group, (iii)optionally substituted C₁-C₆ alkyl, (iv) optionally substituted C₃-C₇cycloalkyl, (v) formyl, (vi) C₂-C₇ alkylcarbonyl, (vii) optionallysubstituted aryl, (viii) optionally substituted heteroaryl, (ix)optionally substituted aralkyl, (x) optionally substitutedheteroarylalkyl, or (xi) an optionally substituted 3 to 7 memberedhetero ring, or R⁴ and R⁵ are taken together with the nitrogen atom toform pyrrolidine, piperidine or azepam).

-   (2) A carbapenem compound or a pharmaceutically acceptable salt    thereof represented by the following formula [1-a] wherein G is G1    in the above formula [1]:

wherein R¹ and R are the same as defined above.

-   (3) A carbapenem compound or a pharmaceutically acceptable salt    thereof represented by the following formula [1-b] wherein G1 is    4-methoxyphenyl in the compound described in above (2):

wherein R¹ and R are the same as defined above.

-   (4) A carbapenem compound or a pharmaceutically acceptable salt    thereof represented by the following formula [1-c] wherein G is G2    in the above formula [1]:

wherein R¹, R and Y¹ are the same as defined above.

-   (5) A carbapenem compound or a pharmaceutically acceptable salt    thereof represented by the following formula [1-d] wherein G is G3    in the above formula [1]:

wherein R¹, R, A, R⁰ and Y² are the same as defined above.

-   (6) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein a group which    reproduces carboxyl group by hydrolysis in vivo is a group of the    formula [4]:

wherein R⁶ is hydrogen atom or C₁-C₆ alkyl, R⁷ is optionally substitutedC₁-C₁₀ alkyl, or optionally substituted C₃-C₁₀ cycloalky, and n is aninteger of 0 or 1.

-   (7) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein R is a group of a    formula [4] in above (6).-   (8) A carbapenem compound described in above (1) to (7) or a    pharmaceutically acceptable salt thereof wherein R¹ is    1-hydroxyethyl.-   (9) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein R is    pivaloyloxymethyl, acetyloxymethyl, acetyloxy-1-ethyl,    isopropyloxycarbonyloxy-1-ethyl or cyclohexyloxycarbonyloxy-1-ethyl.-   (10) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein R is    pivaloyloxymethyl.-   (11) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein R is phthalidyl or    (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.-   (12) A carbapenem compound described in above (1) to (5) or a    pharmaceutically acceptable salt thereof wherein R is hydrogen atom.-   (13) A carbapenem compound described in above (4) or a    pharmaceutically acceptable salt thereof wherein Y¹ is C₂-C₄ alkoxy,    —(CH₂)_(ma)—O—CH₃ (in which ma is an integer of 1˜3) or    —O—(CH₂)_(ma)—O—(CH₂)_(mb—CH) ₃ (in which ma and mb are the same as    defined above).-   (14) A carbapenem compound described in above (4) or a    pharmaceutically acceptable salt thereof wherein Y¹ is C₁-C₄ alkyl,    trifluoromethoxy, halogen atom or cyano.-   (15) A carbapenem compound described in above (4) or a    pharmaceutically acceptable salt thereof wherein Y¹ is —SO₂NR²R³ (in    which R² and R³ are the same as defined above).-   (16) A carbapenem compound described in above (4) or a    pharmaceutically acceptable salt thereof wherein Y¹ is ethoxy,    —CH₂—O—CH₃, —(CH₂)₂—O—CH₃ or —O—(CH₂)₂—O—CH₃.-   (17) A carbapenem compound described in above (4) or (13) to (16) or    a pharmaceutically acceptable salt thereof wherein Y¹ on benzene    ring is metha or para to the binding position of    7-oxo-1-azabicyclo[3.2.0]hept-2-ene.-   (18) A carbapenem compound described in above (4) or (13) to (16) or    a pharmaceutically acceptable salt thereof wherein Y¹ on benzene    ring is para to the binding position of    7-oxo-1-azabicyclo[3.2.0]hept-2-ene.-   (19) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof wherein R⁰ is a formula    [2]:

wherein R^(2a) and R^(3a) are the same as defined above.

-   (20) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof, wherein R⁰ is a formula    [3]:

wherein m and R^(3b) are the same as defined above.

-   (21) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof wherein Y² is C₁-C₄ alkyl.-   (22) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof wherein Y² is C₁-C₄ alkoxy.-   (23) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof wherein Y² is halogen atom    or cyano.-   (24) A carbapenem compound described in above (5) or a    pharmaceutically acceptable salt thereof wherein Y² is —NR⁴R⁵ (in    which R⁴ and R⁵ are the same as defined above).-   (25) A medicament containing a carbapenem compound described in    above (1) to (24) or a pharmaceutically acceptable salt thereof as    an active ingredient.-   (26) An antibacterial agent containing a carbapenem compound    described in above (1) to (24) or a pharmaceutically acceptable salt    thereof as an active ingredient.-   (27) An oral medicament containing a carbapenem compound described    in above (1) to (24) or a pharmaceutically acceptable salt thereof    as an active ingredient.-   (28) An oral antibacterial agent containing a carbapenem compound    described in above (1) to (24) or a pharmaceutically acceptable salt    thereof as an active ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION

“C₁-C₃ alkyl” in R¹ includes, for example, straight or branched C₁-C₃alkyl, such as methyl, ethyl, n-propyl, isopropyl, preferably ethyl orisopropyl.

“C₁-C₃ alkyl substituted by hydroxy” in R¹ includes, for example hydroxyC₁-C₃ alkyl, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxyl-methylethyl, 1-hydroxypropyl, preferably 1-hydroxyethyl,2-hydroxyethyl or 1-hydroxy-1-methylethyl, and especially preferably1-hydroxyethyl.

“C₁-C₄ alkyl” in Y¹ includes, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, preferably methyl, ethyl,n-propyl or isopropyl, and especially preferably methyl or ethyl.

“C₂-C₄ alkoxy” in Y¹ includes, for example, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, preferablyethoxy, n-propoxy or isopropoxy and especially preferably ethoxy.

“Halogen atom” in Y¹ includes fluorine atom, chlorine atom, bromine atomor iodine atom, preferably fluorine atom, chlorine atom and especiallypreferably fluorine atom.

“Lower alkyl” wherein Y¹ is —SO₂NR²R³ (in which R² and R³ areindependently hydrogen atom, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl, or optionally substitutedheteroarylalkyl, or R² and R³ may be taken together with the nitrogenatom to form a 3 to 7 membered hetero ring which may be substituted.),includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, preferably methyl, ethyl, n-propyl or isopropyl, andespecially preferably methyl or ethyl.

“Aryl” moiety in “optionally substituted aryl” includes for example,phenyl or naphthyl and especially preferably phenyl.

“Heteroaryl” moiety in “optionally substituted heteroaryl” includes, forexample, a 5 to 10 membered monocyclic or fused polycyclic aromatic ringcontaining 1 to 3 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom, such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, indolyl, benzothiazolyl, quinazolinyl orisoquinazolinyl, preferably pyridyl, pyrimidinyl, pyridazinyl, thienyl,furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl or triazolyl and especially preferably pyridyl, thienyl,furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl.

“Aralkyl” moiety in “optionally substituted aralkyl” includes such asbenzyl, phenylethyl or naphthylmethyl, and preferably benzyl orphenylethyl.

“Heteroarylalkyl” moiety in “optionally substituted heteroarylalkyl”includes, for example, a group consisting a combination of a C₁-C₃alkylene chain and a 5 to 10 membered monocyclic or fused polycyclicaromatic ring containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom, such as pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, thienylmethyl,furylmethyl, pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, triazolylmethyl,indolylmethyl, benzothiazolylmethyl, qunazolinylmethyl,isoquinazolinylmethyl, pyridylethyl, pyrimidinylethyl, pyridazinylethyl,pyrazinylethyl or pyridylpropyl. Preferable ones are pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl,thiazolylmethyl, isothiazolylmethyl or triazolylmethyl and especiallypreferable ones are pyridylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl orthiazolylmethyl.

“A 3 to 7 membered hetero ring” which R² and R³ are taken together withthe nitrogen atom to form, includes for example, a saturated orunsaturated 3 to 7 heteroring containing 1 to 2 nitrogen atoms, 0 or 1sulfur atom or 0 or 1 oxygen atom, such as aziridine, azetidine,pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine,thiazoline, thiazolidine, morpholine, thiomorpholine, azepane,tetrahydroazepine, tetrahydrodiazepine or hexahydrodiazepine. Thepreferable ones are azetidine, pyrrolidine, tetrahydropyridine,piperazine, thiazoline, thiazolidine, morpholine or thiomorpholine. Theespecially preferable ones are azetidine, pyrrolidine,tetrahydropyridine, thiazoline, thiazolidine or morpholine.

Substitution group in R² and R³ includes, such as hydroxy group, C₁-C₆alkyloxy, C₁-C₆ alkylthio, C₂-C₇ alkylcarbonyl, C₂-C₇ alkylcarbonyloxy,C₂-C₇ alkyloxycarbonyl, C₃-C₇ cycloalkyl, carboxyl, halogen atom, cyano,primary amino, secondary amino or tertiary amino. These substitutiongroups may be protected by a suitable protective group. The substitutionposition(s) are not limited as far as they are chemically possible. Theposition(s) can be single or plural.

“C₁-C₆ alkyloxy” includes, for example straight or branched C₁-C₆ alkoxysuch as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentyloxy or n-hexyloxy, preferably straight or branchedC₁-C₃ alkoxy such as methoxy, ethoxy, n-propoxy or isopropoxy andespecially preferable methoxy or ethoxy.

“C₁-C₆ alkylthio” includes for example, straight or branched C₁-C₆alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio,preferably straight or branched C₁-C₃ alkylthio such as methylthio,ethylthio, n-propylthio or isopropylthio, and especially preferablymethylthio or ethylthio.

“C₂-C₇ alkylcarbonyl” includes for example straight or branched C₂-C₇alkylcarbonyl such as acetyl, propionyl, n-propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl, preferablystraight or branched C₂-C₄ alkylcarbonyl such as acetyl, propionyl,n-propylcarbonyl or isopropylcarbonyl, and especially preferably acetylor propionyl.

“C₂-C₇ alkylcarbonyloxy” includes for example, straight or branchedC₂-C₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy orn-hexylcarbonyloxy, preferably straight or branched C₂-C₄alkylcarbonyloxy such as acetyloxy, propionyloxy, n-propylcarbonyloxy orisopropylcarbonyloxy and especially preferably acetyloxy orpropionyloxy.

“C₂-C₇ alkyloxycarbonyl” includes for example, straight or branchedC₂-C₇ alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl orn-hexyloxycarbonyl, preferably straight or branched C₂-C₄alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl or isopropoxycarbonyl and especially preferablymethoxycarbonyl or ethoxycarbonyl.

“C₃-C₇ cycloalkyl” includes C₃-C₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom oriodine atom, preferably fluorine atom or chlorine atom.

R² and R³ include preferably hydrogen atom, optionally substituted C₁-C₆alkyl, optionally substituted aryl which may contain hetero atom in itsring or optionally substituted aralkyl which may contain hetero atom inits ring, preferably hydrogen atom, optionally substituted methyl,optionally substituted ethyl, aryl which may contain hetero atom in itsring, or aralkyl which may contain hetero atom in its ring.

The signal “ma” in Y¹ is an integer of 1˜3, preferably 1 or 2. Thesignal “mb” in Y¹ is an integer of 0˜3, preferably 0 or 1.

“C₁-C₄ alkyl” in Y² includes such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl, preferably methyl, ethyl, n-propyl orisopropyl, and especially preferably methyl or ethyl.

“C₁-C₄ alkoxy” in Y² includes such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferablymethoxy, ethoxy, n-propoxy or isopropoxy, and especially preferablymethoxy or ethoxy.

“Halogen atom” in Y² includes fluorine atom, chlorine atom, bromine atomor iodine atom, preferably fluorine atom or chlorine atom. When Y² is—NR⁴R⁵, the definitions of R⁴ and R⁵ are as follows. As a protectivegroup of amino group are used various protective groups usually used,preferably C₂-C₇ alkoxycarbonyl, such as tert-butoxycarbonyl, C₁-C₅halogenoalkoxycarbonyl, such as 2-iodoethoxycarbonyl or2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted C₂-C₇alkenyloxycarbonyl such as allyloxycarbonyl, aralkyloxycarbonyl such asbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonylor p-nitrobenzyloxycarbonyl, or trialkylsilyl such as trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl. Furthermore, various protectivegroups which reproduce amino group by hydrolysis in vivo can be used.The preferable one is for example,(5-methyl-1,3-dioxolene-2-one-4-yl)methoxycarbonyl.

“C₁-C₆ alkyl” moiety of “optionally substituted C₁-C₆ alkyl” includesfor example, straight or branched C₁-C₆ alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl, n-hexyl,preferably straight or branched C₁-C₃ alkyl such as methyl, ethyl,n-propyl or isopropyl, and especially preferably methyl or ethyl.

“C₃-C₇ cycloalkyl” moiety of “optionally substituted C₃-C₇ cycloalkyl”includes for example, C₃-C₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

“C₂-C₇ alkylcarbonyl” includes straight or branched C₂-C₇ alkylcarbonylsuch as acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonylor n-hexylcarbonyl, preferably acetyl or propionyl.

“Aryl” moiety of “optionally substituted aryl” includes such as phenylor naphthyl, and especially preferably phenyl.

“Heteroaryl” moiety of “optionally substituted heteroaryl” includes, a 5to 10 membered monocyclic or fused polycyclic aromatic ring containing 1to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom such as pyridyl, pyrimidinyl, pyridazinyl, thienyl, furyl,pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, indolyl, benzothiazolyl, quinazolinyl or isoquinazolinyl,preferably pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl,pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl ortriazolyl, and especially preferably pyridyl, pyrazinyl, thienyl, furyl,pyrrolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl.

“Aralkyl” moiety of “optionally substituted aralkyl” includes forexample, benzyl, phenylethyl or naphthylmethyl, preferably benzyl orphenylethyl.

“Heteroarylaliyl” moiety of “optionally substituted heteroarylalkyl”includes for example, a group consisting a combination of a C₁-C₃alkylene chain and a 5 to 10 membered monocyclic or fused polycyclicaromatic ring containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom such as pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl,thiazolylmethyl, isothiazolylmethyl, triazolylmethyl, indolylmethyl,benzothiazolylmethyl, quinazolinylmethyl, isoquinazolinylmethyl,pyridylethyl, pyrimidinylethyl, pyridazinylethyl, pyrazinylethyl orpyridylpropyl. The preferable ones are pyridylmethyl, pyrimidinylmethyl,pyridazinylmethyl, pyrazinylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl,thiazolylmethyl, isothiazolylmethyl, triazolylmethyl, and especiallypreferably pyridylmethyl, pyrazinylmethyl, thienylmethyl, furylmethyl,pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl orthiazolylmethyl.

“A 3 to 7 membered hetero ring” formed with R⁴ and R⁵ includes forexample, a saturated or unsaturated 3 to 7 heteroring containing 1 to 2nitrogen atoms, 0 or 1 sulfur atom or 0 or 1 oxygen atom, such asaziridine, azetidine, pyrrolidine, dihydropyrrole, piperidine,tetrahydropyridine, piperazine, thiazoline, thiazolidine, morpholine,thiomorpholine, azepam, tetrahydroazepine, tetrahydrodiazepine orhexahydrodiazepine. The preferable one is azetidine, pyrrolidine,tetrahydropyridine, piperazine, thiazoline, thiazolidine, morpholine orthiomorpholine and especially preferably azetidine, pyrrolidine,tetrahydropyridine, thiazoline, thiazolidine or morpholine.

The substitution group of “optionally substituted C₁-C₆ alkyl”,“optionally substituted C₃-C₇ cycloalkyl”, “optionally substitutedaryl”, “optionally substituted heteroaryl”, “optionally substitutedaralkyl”, “optionally substituted heteroarylalkyl” and “an optionallysubstituted 3 to 7 membered hetero ring” formed with R⁴ and R⁵,respectively includes hydroxy group, straight or branched C₁-C₆ alkoxy,such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentyloxy or n-hexyloxy, straight or branched C₁-C₆alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio,straight or branched C₂-C₇ alkylcarbonyl, such as acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl, straight orbranched C₂-C₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy orn-hexylcarbonyloxy, straight or branched C₂-C₇ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl or n-hexyloxycarbonyl, C₃-C₇ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,optionally protected carboxyl, halogen atom such as fluorine atom,chlorine atom, bromine atom or iodide atom, cyano, —NR^(b)R^(c),—CONR^(b)R^(c), —OCONR^(b)R^(c), —CONR^(b)SO₂R^(c), —SO₂NR^(b)R^(c),—NR^(b)SO₂NR^(b)R^(c), or —NR^(b)CONR^(b)R^(c) (in which R^(b) and R^(c)are independently (i) hydrogen atom, (ii) a protective group of aminogroup, (ii) C₁-C₆ alkyl, (iv) C₃-C₇ cycloalkyl, (v) aryl, (vi)heteroaryl, (vii) aralkyl, (viii) heteroarylalkyl, or (ix) a 3 to 7membered hetero ring, or R^(b) and R^(c) are taken together with thenitrogen atom to form pyrrolidine, piperidine or azepane, and thedefinitions of “C₁-C₆ alkyl”, “C₃-C₇ cycloalkyl”, “aryl”, “heteroaryl”,“aralkyl”, “heteroarylalkyl”, and “a 3 to 7 membered hetero ring” inR^(b) and R^(c) are the same as the definitions of R⁴ and R⁵).

These substitution groups may be protected with a suitable protectivegroup. The substitution position(s) are not limited as far as these arechemically possible, and are single or plural.

When R⁰ is the formula [2], the definitions of R^(2a) and R^(3a) are asfollows.

“C₁-C₆ alkyl” moiety of “optionally substituted C₁-C₆ alkyl” includesfor example, straight or branched C₁-C₆ alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl,preferably straight or branched C₁-C₃ alkyl such as methyl, ethyl,n-propyl or isopropyl, and especially preferably methyl or ethyl.

“C₃-C₇ cycloalkyl” moiety of “optionally substituted C₃-C₇ cycloalkyl”includes for example, C₃-C₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

“Aryl” of “optionally substituted aryl” includes such as phenyl ornaphthyl, and especially preferably phenyl.

“Heteroaryl” of “optionally substituted heteroaryl” includes forexample, a 5 to 10 membered monocyclic or fused polycyclic aromatic ringcontaining 1 to 3 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, indolyl, benzothiazolyl, quinazolinyl orisoquinazolinyl, preferably pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl or triazolyl, and especially preferably pyridyl,pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl orthiazolyl.

“Aralkyl” moiety of “optionally substituted aralkyl” includes such asbenzyl, phenylethyl or naphthylmethyl, preferably benzyl or phenylethyl.

“Heteroarylalkyl” moiety of “optionally substituted heteroarylalkyl”includes for example, a group consisting a combination of a C₁-C₃alkylene chain and a 5 to 10 membered monocyclic or fused polycyclicaromatic ring containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom such as pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, thienylmethyl,furylmethyl, pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, triazolylmethyl,indolylmethyl, benzothiazolylmethyl, quinazolinylmethyl,isoquinazolinylmethyl, pyridylethyl, pyrimidinylethyl, pyridazinylethyl,pyrazinylethyl or pyridylpropyl. The preferable ones are pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, thienylmethyl,furylmethyl, pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl ortriazolylmethyl, and especially preferably pyridylmethyl,pyrazinylmethyl, thienylmethyl, furylmethyl, pyrrolylmethyl,imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl or thiazolylmethyl.

“A 3 to 7 membered hetero ring” and “an optionally substituted 3 to 7membered hetero ring” formed with R^(2a) and R^(3a) includes, forexample, a saturated or unsaturated 3 to 7 hetero ring containing 1 to 2nitrogen atoms, 0 or 1 sulfur atom or 0 or 1 oxygen atom, such asaziridine, azetidine, pyrrolidine, dihydropyrrole, piperidine,tetrahydropyridine, piperazine, thiazoline, thiazolidine, morpholine,thiomorpholine, azepane, tetrahydroazepine, tetrahydrodiazepine orhexahydrodiazepine. The preferred one is azetidine, pyrrolidine,tetrahydropyridine, piperazine, thiazoline, thiazolidine, morpholine orthiomorpholine, and especially preferably azetidine, pyrrolidine,tetrahydropyridine, thiazoline, thiazolidine or morpholine.

The substitution group of “optionally substituted C₁-C₆ alkyl”,“optionally substituted C₃-C₇ cycloalkyl”, “optionally substitutedaryl”, “optionally substituted heteroaryl”, “an optionally substitutedaralkyl”, “optionally substituted heteroarylalkyl” and “optionallysubstituted 3 to 7 membered hetero ring” formed with R^(2a) and R^(3a),respectively includes hydroxy group, straight or branched C₁-C₆ alkoxy,such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentyloxy or n-hexyloxy, straight or branched C₁-C₆alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio,straight or branched C₂-C₇ alkylcarbonyl, such as acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl, straight orbranched C₂-C₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy orn-hexylcarbonyloxy, straight or branched C₂-C₇ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl or n-hexyloxycarbonyl, C₃-C₇ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,optionally protected carboxyl, halogen atom such as fluorine atom,chlorine atom, bromine atom or iodide atom, cyano, —NR^(d)R^(e),—CONR^(d)R^(e), —OCONR^(d)R^(e), —CONR^(d)SO₂R^(e), —SO₂NR^(d)R^(e),—NR^(d)SO₂NR^(d)R^(e), or —NR^(d)CONR^(d)R^(e) (in which R^(d) and R^(e)are independently

(i) hydrogen atom, (ii) a protective group of amino group, (iii) C₁-C₆alkyl, (iV) C₃-C₇ cycloalkyl, (v) aryl, (vi) heteroaryl, (vii) aralkyl,(viii) heteroarylalkyl, or (ix) a 3 to 7 membered hetero ring, or R^(b)and R^(c) are taken together with the nitrogen atom to form pyrrolidine,piperidine or azepane, and the definitions of “C₁-C₆ alkyl”, “C₃-C₇cycloalkyl”, “aryl”, “heteroaryl”, “aralkyl”, “heteroarylalkyl”, and “a3 to 7 membered hetero ring” in R^(d) and R^(e) are the same as thedefinitions of R^(2a) and R^(3a).). These substituents may be protectedwith a suitable protective group. The substitution position(s) are notlimited as far as these are chemically possible, and are single orplural.

When R⁰ is the formula [3], the definition of R^(3a) is as follows.

“C₁-C₆ alkyl” moiety of “optionally substituted C₁-C₆ alkyl” includesfor example, straight or branched C₁-C₆ alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl,preferably straight or branched C₁-C₃ alkyl such as methyl, ethyl,n-propyl or isopropyl and especially preferably methyl or ethyl.

“C₃-C₇ cycloalkyl” moiety of “optionally substituted C₃-C₇ cycloalkyl”includes for example, C₃-C₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

“Aryl” of “optionally substituted aryl” includes such as phenyl ornaphthyl, and especially preferably phenyl.

“Heteroaryl” of “optionally substituted heteroaryl” includes forexample, a 5 to 10 membered monocyclic or fused polycyclic aromatic ringcontaining 1 to 3 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, indolyl, benzothiazolyl, quinazolinyl orisoquinazolinyl, preferably pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl or triazolyl, and especially preferably pyridyl,pyrazinyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl orthiazolyl.

“Aralkyl” moiety of “optionally substituted aralkyl” includes such asbenzyl, phenylethyl or naphthylmethyl, preferably benzyl or phenylethyl.

“Heteroarylalkyl” moiety of “optionally substituted heteroarylalkyl”includes for example, a group consisting a combination of a C₁-C₃alkylene chain and a 5 to 10 membered monocyclic or fused polycyclicaromatic ring containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom such as pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, thienylmethyl,furylmethyl, pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, triazolylmethyl,indolylmethyl, benzothiazolylmethyl, quinazolinylmethyl,isoquinazolinylmethyl, pyridylethyl, pyrimidinylethyl, pyridazinylethyl,pyrazinylethyl or pyridylpropyl. The preferable one is pyridylmethyl,pyrimidinylmethyl, pyridazinylmethyl, pyrazinylmethyl, thienylmethyl,furylmethyl, pyrrolylmethyl, imidazolylmethyl, oxazolylmethyl,isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl ortriazolylmethyl, and especially preferably pyridylmethyl,pyrazinylmethyl, thienylmethyl, furylmethyl, pyrrolylmethyl,imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl or thiazolylmethyl.

“A 3 to 7 membered hetero ring” of “an optionally substituted 3 to 7membered hetero ring” includes, for example, a saturated or unsaturated3 to 7 heteroring containing 1 to 2 nitrogen atoms, 0 or 1 sulfur atomor 0 or 1 oxygen atom, such as aziridine, azetidine, pyrrolidine,dihydropyrrole, tetrahydropyridine, piperidine, piperazine, thiazoline,thiazolidine, morpholine, thiomorpholine, azepane, tetrahydroazepine,tetrahydrodiazepine, or hexahydrodiazepine. The preferred one isazetidine, pyrrolidine, tetrahydropyridine, piperazine, thiazoline,thiazolidine, morpholine or thiomorpholine, and especially preferablyazetidine, pyrrolidine, tetrahydropyridine, thiazoline, thiazolidine ormorpholine.

The substitution group of “optionally substituted C₁-C₆ alkyl”,“optionally substituted C₃-C₇ cycloalxyl”, “optionally substitutedaryl”, “optionally substituted heteroaryl”, “optionally substitutedaralkyl”, “optionally substituted heteroarylalkyl” and “optionallysubstituted 3 to 7 membered hetero ring” in R^(3b), respectivelyincludes hydroxy group, straight or branched C₁-C₆ alkoxy, such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentyloxy or n-hexyloxy, straight or branched C₁-C₆alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio,straight or branched C₂-C₇ alkylcarbonyl, such as acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl, straight orbranched C₂-C₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy orn-hexylcarbonyloxy, straight or branched C₂-C₇ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl or n-hexyloxycarbonyl, C₃-C₇ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,optionally protected carboxyl, halogen atom such as fluorine atom,chlorine atom, bromine atom or iodide atom, cyano, —NR^(d)R^(e),—CONR^(d)R^(e), —OCONR^(d)R^(e), —CONR^(d)SO₂R^(e), —SO₂NR^(d)R^(e),—NR^(d)SO₂NR^(d)R^(e), or —NR^(d)CONR^(d)R^(e) (in which R^(d) and R^(e)are the same as defined above). These substitution groups may beprotected with a suitable protective group. The substitution position(s)are not limited as far as these are chemically possible, and are singleor plural.

“A group which reproduces carboxyl group by hydrolysis in vivo” inR^(3b) which is possible only in the case that m is 1 includes any groupas far as it reproduces carboxyl group by hydrolysis in vivo, and meansthe group used when derived into the compound called a prodrug. Thepreferable ones are C₁-C₆ alkyl, such as, methyl or ethyl, C₂-C₁₂alkoxyalkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl,2-methoxyethoxymethyl, phthalidyl,2-(4-morpholinyl)ethyl,(2-oxo-1,3-dioxol-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-t-butyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl, pivaloyloxymethyl,acetyloxymethyl, acetyloxyl-ethyl, cyclohexylacetyloxymethyl,1-methylcyclohexylcarbonyloxymethyl, ethoxycarbonyloxyl-ethyl orcyclohexyloxycarbonyloxyl-ethyl, especially preferably, phthalidyl or(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, pivaloyloxymethyl.

When A is —(CH₂)_(s)—NR^(a)—(CH₂)_(t)—(in which s and t are the same asdefined above, R^(a) is hydrogen atom, a protective group of amino groupor optionally substituted C₁-C₆ alkyl), a protective group of aminogroup in R^(a) includes various protective groups usually used,preferably such as C₂-C₇ alkoxycarbonyl such as tert-butoxycarbonyl,C₁-C₅ halogenoalkoxycarbonyl such as 2-iodoethoxycarbonyl or2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted C₂-C₇alkenyloxycarbonyl such as allyloxycarbonyl, aralkyloxycarbonyl such asbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonylor p-nitrobenzyloxycarbonyl, or trialkylsily such as trimethylsilyl,triethylsilyl or tert-butyldimethylsilyl. Furthermore, variousprotective groups which reproduce amino group by hydrolysis in vivo canbe used. The preferable one is for example,(5-methyl-1,3-dioxolene-2-one-4-yl)methoxycarbonyl.

“C₁-C₆ alkyl” includes for example, straight or branched C₁-C₆ alkylsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl, preferably straight or branched C₁-C₃alkyl such as methyl, ethyl, n-propyl or isopropyl, and especiallypreferably methyl or ethyl.

The substituted group of “optionally substituted C₁-C₆ alkyl” in R^(a)includes hydroxy group, straight or branched C₁-C₆ alkoxy, such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentyloxy or n-hexyloxy, straight or branched C₁-C₆alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio,straight or branched C₂-C₇ alkylcarbonyl, such as acetyl, propionyl,n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl, straight orbranched C₂-C₇ alkylcarbonyloxy, such as acetyloxy, propionyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy orn-hexylcarbonyloxy, straight or branched C₂-C₇ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,n-pentyloxycarbonyl or n-hexyloxycarbonyl, C₃-C₇ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,optionally protected carboxyl, halogen atom such as fluorine atom,chlorine atom, bromine atom or iodide atom, cyano, —NR^(d)R^(e),—CONR^(d)R^(e), —OCONR^(d)R^(e), —CONR^(d)SO₂R^(e), —SO₂NR^(d)R^(e),—NR^(d)SO₂NR^(d)R^(e), or —NR^(d)CONR^(d)R^(e) (in which R^(d) and R^(e)are the same as defined above).

The signal “r” in A is an integer of 1˜3, preferably 1, 2.

The signal “s” in A is an integer of 1˜3, preferably 0, 1, 2.

The signal “t” in A is an integer of 1˜3, preferably 0, 1, 2.

“A group which reproduces carboxyl group by hydrolysis in vivo” in Rincludes any group as far as it reproduces carboxyl group by hydrolysisin vivo, and means the group used when derived into the compound calleda prodrug. The preferable group is a formula [4]:

wherein R⁶, R⁷ and n are the same as defined above.

“C₁-C₆ alkyl” in R⁶ includes for example, straight or branched C₁-C₆alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl, and preferably methyl.

“C₁-C₁₀ alkyl” in R⁷ includes straight or branched C₁-C₁₀ alkyl such asmethyl, ethyl, n-propyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl or n-decyl, and preferably, methyl, ethyl,n-propyl, isobutyl, tert-butyl, n-pentyl or n-hexyl.

“C₃-C₁₀ cycloalkyl” in R⁷ includes such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl orcyclodecyl, and preferably, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

The substitution group of “optionally substituted C₁-C₁₀ alkyl” and“optionally substituted C₃-C₁₀ cycloalkyl” in R⁷ includes straight orbranched C₁-C₆ alkyl such as methyl, ethyl, n-propyl, isobutyl,tert-butyl, n-pentyl or n-hexyl, and preferably, methyl or ethyl. Thepreferable one of the formula [4] is pivaloyloxymethyl, acetyloxymethyl,acetyloxyl-ethyl, cyclohexylacetyloxymethyl,1-methylcyclohexylcarbonyloxymethyl, ethoxycarbonyloxyl-ethyl orcyclohexyloxycarbonyloxyl-ethyl, and especially preferablypivaloyloxymethyl.

Other example of “a group which reproduces carboxyl group by hydrolysisin vivo” in R is C₁-C₆ alkyl such as methyl or ethyl, C₂-C₁₂ alkoxyalkylsuch as methoxymethyl, ethoxymethyl, 2-methoxyethyl,2-methoxyethoxymethyl, phthalidyl, 2-(4-morpholinyl)ethyl,(2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-t-butyl-2-oxo-1,3-dioxol-4-yl)methyl or(5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl, and especially preferably,phthalidyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

The protective group of carboxyl includes various protective groupsusually used, preferably straight or branched C₁-C₆ alkyl, such asmethyl, ethyl, isopropyl or tert-butyl, C₁-C₆ halogenoalkyl, such as2-iodoethyl or 2,2,2-trichloroethyl, C₂-C₇ alkoxymethyl such asmethoxymethyl, ethoxymethyl or isobutoxymethyl, C₂-C₇alkylcarbonyloxymethyl such as acetyloxymethyl, propionyloxymethyl,butyryloxymethyl or pivaloyloxymethyl, C₄-C₁₁ 1-alkoxycarbonyloxyethylsuch as 1-ethoxycarbonyloxyethyl, aralkyl group such as benzyl,p-methoxybenzyl, o-nitrobenzyl or p-nitrobenzyl, C₃-C₇ alkenyl such asallyl or 3-methylallyl, benzhydryl, phthalidyl,(2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-t-butyl-2-oxo-1,3-dioxol-4-yl)methyl, or(5-phenyl2-oxo-1,3-dioxol-4-yl)methyl.

The protective group of hydroxy group or amino group includes variousprotective groups usually used, preferably for example, C₂-C₇alkoxycarbonyl, such as tert-butoxycarbonyl, C₁-C₅halogenoalkoxycarbonyl such as 2-iodoethoxycarbonyl or2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted C₂-C₇alkenyloxycarbonyl such as allyloxycarbonyl, aralkyloxycarbonyl such asbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonylor p-nitrobenzyloxycarbonyl, or trialkylsily such as trimethylsilyl,triethylsilyl or tert-butyldimethylsilyl. Furthermore, variousprotective groups which reproduce hydroxy group and/or amino group byhydrolysis in vivo can be used, preferably for example,(5-methyl-1,3-dioxolene-2-one-4-yl)methoxycarbonyl can be used.

The pharmaceutically acceptable salt of the carbapenem compound of thepresent invention is a conventional non-toxic salt. Such a saltincludes, as a salt with a carboxyl group in the molecule, a salt withan inorganic base such as sodium, potassium, calcium or magnesium,ammonium, or a salt with an organic base such as triethylammonium,pyridinium or diisopropylammonium. As a salt with a basic group in themolecule, a salt with an inorganic acid such as hydrochloric acid,sulfuric acid or phosphoric acid, or a salt with an organic acid such asformic acid, acetic acid, oxalic acid, methanesulfonic acid orbenzenesulfonic acid can be exemplified.

The pharmaceutically acceptable salt of the carbapenem compound of thepresent invention may be in the form of an anhydride thereof, or ahydrate thereof, or a solvate thereof.

The second aspect of the present invention relates to a pharmaceuticalcomposition containing a carbapenem compound as an active ingredient.

Since the carbapenem compound of the present invention has a potentantibacterial activity, excellent oral absorbability and furthermore,has stability to DHP-1, the compound is expected as a potentantibacterial agent which is clinically applicable, especially an orallyantibacterial agent.

The carbapenem compound of the present invention exhibits broadantibacterial spectrum including gram positive bacteria, such asStaphylococcus aureus, Staphylococcus epidermidis, Streptococcuspyogenes, Streptococcus pneumoniae, Enterococcus faecalis, etc., andgram negative bacteria, such as Escherichia coli, the genus Proteus,Klebsiella pneumoniae, Haemophilus influenzae, Neisseria gonorrhea, thegenus Branhamella, etc. The carbapenem compound of the present inventionhas been found to have a potent antibacterial activity especiallyagainst penicillin resistant Streptococcus pneumoniae (PRSP) orHaemophilus influenzae (which widely gain resistance to known β-lactamagents by mutation of a penicillin binding protein (PBP) such asβ-lactamase non-producing ampicillin resistant Haemophilus influenzae(BLNAR), which have been recently increasingly isolated and provide aclinical trouble.).

It is well known that dehydropeptidase-I (DHP-I), a renal enzyme caneasily hydrolyze a carbapenem derived from natural sources. Some of thepresent carbapenem compounds show resistance to DHP-I and it is possibleto use them solely. However, it is possible to use the compound of thepresent invention together with a DHP-I inhibitor, if necessary.

When used as an antibacterial agent in the treatment of infectiousdiseases caused by bacteria, the carbapenem compounds of the presentinvention are administered, for example, orally in the form of a tablet,a capsule, powders, syrup, etc. or parenterally such as intravenousinjection, intramuscular injection, or intrarectal administration.

The suitable administration forms as mentioned above may be prepared ina conventional manner by mixing an active ingredient with apharmaceutically acceptable carrier, excipient, binder, stabilizer, etc.When administered in the form of injection, a pharmaceuticallyacceptable buffering agent, solubilizer, isotonic agent, etc. may beadded thereto.

The dosage of the compound varies according to the symptoms, ages, bodyweights, the administration form, the frequency of the administration,etc., but it is usually in the range of 100 to 3000 mg per day for anadult, which is administered once or divided into several dosage units.Besides, the dosage of the compound may be increased or decreased, ifnecessary.

The carbapenem compound of the present invention is prepared by variousknown methods (Tetrahedron, 39, 2531-2549 (1983), Tetrahedron Letters,31, 2853-2856 (1990), ibid. 34, 3211-3214 (1993), ibid. 36, 4563-4566(1995), Japanese patent publication B 4-40357, WO 02/053566, WO03/040146, WO 03/089431, etc.). One of these methods, for example isillustrated as follows:

The compound of the formula [1-a] is prepared by for example, process(1) mentioned below.

In the above formulas, R¹, R⁶ and R⁷ are the same as defined above, R⁸is a protective group of carboxyl group or group which reproducescarboxyl group by hydrolysis in vivo, R^(1a) and R^(1b) areindependently C₁-C₃ alkyl group or C₁-C₃ alkyl substituted by protectedhydroxy group. Z is chlorine atom, bromine atom or iodine atom.

Step 1: Process for Preparation of Compound 4

Compound 4 is prepared by reacting compound 2 and compound 3 in thepresence of acid catalyst in an inert solvent. The acid catalystincludes zinc chloride, zinc bromide, zinc iodide, tin tetrachloride,trifluoromethanesulfonic acid trimethylsilyl ester or borontrifluoride-diethyl ether complex.

The inert solvent includes dichloromethane, 1,2-dichloroethane,acetonitrile, monochlorobenzene, dioxane, tetrahydrofuran, benzene ortoluene.

The reaction is carried out at −78° C. to 60° C., preferably at −30° C.to 40° C. The starting compound 3 is prepared by enol-etherification ofvarious actetophenone derivatives prepared by known methods (e.g.Synthesis and reaction of organic compound [II] page 751-875 (1977), SinJikken Kagaku Kouza edited by The Chemical Society of Japan, Vol. 14(Maruzen), or Organic Synthesis [III], Aldehyde-Ketone-Quinone, page149-353 (1991), Sin Jikken Kagaku Kouza edited by The Chemical Societyof Japan, 4th Edition (Maruzen)).

Step 2: Process for Preparation of Compound 6

Corresponding hemiacetal is prepared by heating compound 4 and compound5A under dehydrating condition in an inert solvent. The inert solventincludes dichloromethane, 1,2-dichloroethane, monochlorobenzene,benzene, toluene or xylene. The reaction was carried out at 50° C. to200° C., preferably at 80° C. to 150° C. In accordance of the knownmethod (the Journal of Organic Chemistry, 61, 7889-7894 (1996)) thecorresponding hemiacetal compound is also prepared by reacting compound4 and compound 5B in the presence of a base in an inert solvent,followed by reduction to give an imido compound. The base includestriethylamine, diisopropylethylamine or N-methylmorpholine. The inertsolvent for imidation includes dichloromethane, 1,2-dichloroethane ormonochiorobenzene. The imidation was carried out at −50° C. to 50° C.,preferably at −30° C. to 30° C., The preferable reducing agent is zincand the reduction is carried out in a mixed solvent such as acetic acidand dichloromethane, acetic acid and 1,2-dichloroethane, and acetic acidand monochlorobenzene at −50° C. to 50° C., preferably at −30° C. to 30°C.

Thus obtained hemiacetal compound is chlorinated using a chlorinatingagent such as thionyl chloride, oxalyl chloride or phosphorousoxychloride. The chlorination is conducted in an inert solvent such asether, tetrahydrofuran or dichloromethane, in the presence of a basesuch as lutidine, pyridine, quinoline, diisopropylethylamine ortriethylamine at −78° C. to 60° C., preferably at −30° C. to 40° C.

Step 3: Process for Preparation of Compound 7

Compound 7 is prepared by reacting compound 6 and triphenylphosphine inan inert solvent such as tetrahydrofuran, dioxane, or dimethoxyethane inthe presence of a base such as lutidine, pyridine, quinoline,dilsopropylethylamine or triethylamine at 0° C. to 100° C., preferablyat 10° C. to 70° C.

Step 4: Process for Preparation of Compound 8

If necessary, the protective group of hydroxy group in R^(1a) is removedand followed by reprotection. The removal of the protective group andprotection are known (for example, see T. W. Greene, P. G. M. Wuts:Protective Groups in Organic Synthesis; 3rd ed., Wiley, New York (1999),or P. Kocienski, Protecting Groups, Thieme, Stuttgart (1994)).

Step 5: Process for Preparation of Compound 9

Compound 9 is prepared by cyclizing compound 8 in an inert solvent suchas benzene, toluene or xylene at 80° C. to 200° C.

Step 6: Process for Preparation of Compound [1-a] (R is Hydrogen Atom)

Carbapenem compound [1-a] (R is hydrogen atom) is prepared by removing aprotective group of carboxyl group in R⁸ of compound 9, or removing aprotective group of hydroxy group when R^(1b) is a protective group ofhydroxy group. The removal of the protective group is carried out byknown method such as treating with acid base, reduction agent (see T. W.Greene, P. G. M. Wuts: Protective Groups in Organic Synthesis; 3rd ed.,Wiley, New York (1999), or P. Kocienski, Protecting Groups, Thieme,Stuttgart (1994)).

Step 7: Process for Preparation of Compound [1-a] (R is a Group whichReproduces Carboxyl group by Hydrolysis in Vivo)

Compound [1-a] (R is a group which reproduces carboxyl group byhydrolysis in vivo) is prepared by introducing using a conventionalmethod, a group which reproduces carboxyl group by hydrolysis in vivointo carbapenem compound [1-a] (R is hydrogen atom). For example,carbapenem compound [1-a] (R is hydrogen atom) or its carboxylic acidsalt is reacted with various halides of the compound 10, if necessary,in the presence of a base such as diisopropylethylamine, triethylamine,4-dimethylaminopyridine, potassium carbonate or sodiumhydrogencarbonate, or phase transfer catalyst such astriethylbenzylammoniun chloride or tetrabutylammonium bromide. Thereaction solvent is not limited as far as it is inert and preferablydimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide,acetonitrile, dioxane, tetrahydrofuran or acetone. The carboxylic acidsalt includes preferably its sodium or potassium salt. The reaction iscarried out at −78° C. to 100° C., preferably −20° C. to 60° C.Furthermore, in step 2, using compound 5A or 5B having a group whichreproduces carboxyl group by hydrolysis in vivo in R⁸, and then, viaeach step, carbapenem compound [1-a] (R is a group which reproducescarboxyl group by hydrolysis in vivo) can be directly prepared.

In the above steps, after reaction the product is isolate by the methodaccording to organic chemistry, and when the product is water soluble,the reaction mixture is adjusted to around neutralization and issubjected to column chromatography using absorption resin, etc. and thefractions containing the object compound are taken and lyophilized tothe object compound.

The compound of the formula [1-b] is prepared in accordance of process(1).

The compound of the formula [1-c] is prepared, for example by process(2).

In the above formulas, R¹, R^(1a), R^(1b), R⁶, R⁷, R⁸, Y¹ and Z are thesame as defined above.

Step 8: Process for Preparation of Compound 12

Compound 12 is prepared by reacting compound 2 and compound 11 in thepresence of acid catalyst in an inert solvent. The acid catalystincludes zinc chloride, zinc bromide, zinc iodide, tin tetrachloride,trifluoromethanesulfonic acid trimethylsilyl ester or borontrifluoride-diethylether complex.

The inert solvent includes dichloromethane, 1,2-dichloroethane,acetonitrile, monochlorobenzene, dioxane, tetrahydrofuran, benzene ortoluene.

The reaction is carried out at −78° C. to 60° C., preferably at −30° C.to 40° C. The starting compound 11 is also prepared byenol-etherification of various actetophenone derivatives prepared byknown methods (e.g. Synthesis and reaction of organic compound [II] page751-875 (1977), Sin Jikken Kagaku Kouza edited by The Chemical Societyof Japan, Vol. 14 (Maruzen), or Organic Synthesis [III], Aldehyde KetoneQuinone, page 149-353 (1991), Sin Jikken Kagaku Kouza edited by TheChemical Society of Japan, 4th Edition (Maruzen)).

Step 9: Process for Preparation of Compound 13

Corresponding hemiacetal is prepared by heating compound 12 and compound5A under dehydrating condition in an inert solvent. The inert solventincludes dichloromethane, 1,2-dichloroethane, monochlorobenzene,benzene, toluene or xylene. The reaction was carried out at 50° C. to200° C., preferably at 80° C. to 150° C. In accordance of the knownmethod (the method described in the Journal of Organic Chemistry, 61,7889-7894 (1996)) the corresponding hemiacetal compound is also preparedby reacting compound 12 and compound 5B in the presence of a base in aninert solvent, followed by reduction to give an imido compound, The baseincludes triethylamine, diisopropylethylamine or N-methylmorpholine. Theinert solvent for imidation includes dichloromethane, 1,2-dichloroethaneor monochlorobenzene. The imidation was carried out at −50° C. to 50°C., preferably at −30° C. to 30° C. The reduction is carried out inpreferably zinc, in a mixed solvent such as acetic acid anddichloromethane, acetic acid and 1,2-dichloroethane or acetic acid andmonochlorobenzene at −50° C. to 50° C., preferably at −30° C. to 30° C.

Thus obtained hemiacetal compound is chlorinated using a chlorinatingagent such as thionyl chloride, oxalyl chloride or phosphorousoxychloride. The chlorination is conducted in an inert solvent such asether, tetrahydrofuran or dichloromethane, in the presence of a basesuch as lutidine, pyridine, quinoline, diisopropylethylamine ortriethylamine at −78° C. to 60° C., preferably at −30° C. to 40° C.

Step 10: Process for Preparation of Compound 14

Compound 14 is prepared by reacting compound 13 with triphenylphosphinein an inert solvent such as tetrahydrofuran, dioxane or dimethoxyethane,in the presence of a base such as lutidine, pyridine, quinoline,diisopropylethylamine or triethylamine at 0° C. to 100° C., preferablyat 10° C. to 70° C.

Step 11: Process for Preparation of Compound 15

If necessary, the protective group of hydroxy group in R^(1a) is removedand followed by reprotection. The removal of the protective group orprotecting is known (for example, T. W. Greene, P. G. M. Wuts:Protective Groups in Organic Synthesis; 3rd ed., Wiley, New York (1999),or P. Kocienski, Protecting Groups, Thieme, Stuttgart (1994)).

Step 12: Process for Preparation of Compound 16

Compound 16 is prepared by cyclizing compound 15 in an inert solventsuch as benzene, toluene or xylene at 80° C. to 200° C.

Step 13: Process for Preparation of Compound [1-c] (R is Hydrogen Atom)

Carbapenem compound [1-c] (R is hydrogen atom) is prepared by removing aprotective group of carboxyl group at R⁸ of compound 16, or removing aprotective group of hydroxy group when R^(1b) is a protective group ofhydroxy group. The removal of the protective group is carried out byknown method such as treating with an acid, a base and a reduction agent(see T. W. Greene, P. G. M. Wuts: Protective Groups in OrganicSynthesis; 3rd ed., Wiley, New York (1999), or P. Kocienski, ProtectingGroups, Thieme, Stuttgart (1994)).

Step 14: Process for Preparation of Compound [1-c] (R is a Group Whichreproduces carboxyl group by hydrolysis in vivo)

Compound [1-c] (R is a group which reproduces carboxyl group byhydrolysis in vivo) is prepared by introducing using a conventionalmethod, a group which reproduces carboxyl group by hydrolysis in vivointo carbapenem compound [1-c] (R is hydrogen atom). For example,carbapenem compound [1-c] (R is hydrogen atom) or its carboxylic acidsalt is reacted with various halides of the compound 10, if necessary,in the presence of a base such as diisopropylethylamine, triethylamine,4-dimethylaminopyridine, potassium carbonate or sodiumhydrogencarbonate, or phase transfer catalyst such astriethylbenzylammoniun chloride or tetrabutylammonium bromide. Thereaction solvent is not limited as far as it is inert and preferablydimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide,acetonitrile, dioxane, tetrahydrofuran or acetone. The carboxylic acidsalt includes preferably its sodium or potassium salt. The reaction iscarried out at −78° C. to 100° C., preferably −20° C. to 60° C.Furthermore, in step 9, using compound 5A or 5B having a group whichreproduces carboxyl group by hydrolysis in vivo in R⁸, and then, viaeach step, carbapenem compound [1-c] (R is a group which reproducescarboxyl group by hydrolysis in vivo) can be directly prepared.

In the above steps, after reaction the product is isolate by the methodaccording to organic chemistry, and when the product is water soluble,the reaction mixture is adjusted to around neutralization and issubjected to column chromatography using absorption resin, etc. and thefractions containing the object compound are taken and lyophilized tothe object compound.

The compound of the formula [1-d] is prepared for example, by proceed(3).

In the above formulas R⁰, R¹, R^(1a), R^(1b), R⁶, R⁷, R⁸, A, Y² and Zare the same as defined above, R^(0a) and R^(0b) are hydroxy group, aprotective group of amino group, the formula [2]:

wherein R^(2a) and R^(3a) are the same as defined above, or the formula[3]:

wherein m and R^(3b) are the same as defined above.

Step 15: Process for Preparation of Compound 18

Compound 18 is prepared by reacting compound 2 and compound 17 in thepresence of acid catalyst in an inert solvent. The acid catalystincludes zinc chloride, zinc bromide, zinc iodide, tin tetrachloride,trifluoromethanesulfonic acid trimethylsilyl ester or borontrifluoride-diethyl ether complex.

The inert solvent includes dichloromethane, 1,2-dichloroethane,acetonitrile, monochlorobenzene, dioxane, tetrahydrofuran, benzene ortoluene.

The reaction is carried out at −78° C. to 60° C., preferably at −30° C.to 40° C. The starting compound 17 is prepared by enol-etherification ofvarious actetophenone derivatives prepared by known methods (e.g.Synthesis and reaction of organic compound [II] page 751-875 (1977), SinJikken Kagaku Kouza edited by The Chemical Society of Japan, Vol. 14(Maruzen), or Organic Synthesis [III], Aldehyde-Ketone-Quinone, page149-353 (1991), Sin Jikken Kagaku Kouza edited by The Chemical Societyof Japan, 4th Edition (Maruzen)).

Step 16: Process for Preparation of Compound 19

Corresponding hemiacetal is prepared by heating compound 18 and compound5A under dehydrating condition in an inert solvent. The inert solventincludes dichloromethane, 1,2-dichloroethane, monochlorobenzene,benzene, toluene or xylene. The reaction was carried out at 50° C. to200° C., preferably at 80° C. to 150° C. In accordance of the knownmethod (the method described in the Journal of Organic Chemistry, 61,7889-7894 (1996)) the corresponding hemiacetal compound is also preparedby reacting compound 18 and compound 5B in the presence of a base in aninert solvent, followed by reduction to give an imido compound. The baseincludes triethylamine, diisopropylethylamine or N-methylmorpholine. Theinert solvent for imidation includes dichloromethane, 1,2-dichloroethaneor monochlorobenzene. The imidation was carried out at −50° C. to 50°C., preferably at −30° C. to 30° C. The reduction is carried out inpreferably zinc, in a mixed solvent such as a mixture of acetic acid anddichloromethane, a mixture of acetic acid and 1 ,2-dichloroethane or amixture of acetic acid and monochlorobenzene at −50° C. to 50° C.,preferably at −30° C. to 30° C.

Thus obtained hemiacetal compound is chlorinated using a chlorinatingagent such as thionyl chloride, oxalyl chloride or phosphorousoxychloride. The chlorination is conducted in an inert solvent such asether, tetrahydrofuran or dichloromethane, in the presence of a basesuch as lutidine, pyridine, quinoline, diisopropylethylamine ortriethylamine at −78° C. to 60° C., preferably at −30° C. to 40° C.

Step 17: Process for Preparation of Compound 20

Compound 20 is prepared by reacting compound 19 with triphenylphosphinein an inert solvent such as tetrahydrofuran, dioxane or dimethoxyethane,in the presence of a base such as lutidine, pyridine, quinoline,diisopropylethylamine or triethylamine at 0° C. to 100° C., preferablyat 10° C. to 70° C.

Step 18: Process for Preparation of Compound 21

If necessary, the protective group of hydroxy group in R^(1a) and aprotective group in R^(0a) are removed and followed by reprotecting. Theremoval of the protective group or protecting is known (for example seeT. W. Greene, P. G. M. Wuts: Protective Groups in Organic Synthesis; 3rded., Wiley, New York (1999), or P. Kocienski, Protecting Groups, Thieme,Stuttgart (1994).

Step 19: Process for Preparation of Compound 22

Compound 22 is prepared by cyclizing compound 21 in an inert solventsuch as benzene, toluene or xylene at 80° C. to 200° C.

Step 20: Process for Preparation of Compound 23

Compound 23 is prepared by removing a protective group in R^(0b) ofcompound 22, if necessary, followed by known chemical reaction(acylation, carbamate-formation, urea-formation). The removal of theprotective group is carried our by known method (for example, see T. W.Greene, P. G. M. Wuts: Protective Groups in Organic Synthesis; 3rd ed.,Wiley, New York (1999), or P. Kocienski, Protecting Groups, Thieme,Stuttgart (1994)).

Step 21: Process for preparation of compound [1-d] (R is Hydrogen Atom)

Carbapenem compound [1-d] (R is hydrogen atom) is prepared by removing aprotective group of carboxyl group in R⁸ of compound 23, or removing aprotective group of hydroxy group when R^(1b) is a protective group ofhydroxy group. The removal of the protective group is carried out byknown method such as treating with acid base, reduction agent (see suchas T. W. Greene, P. G. M. Wuts: Protective Groups in Organic Synthesis;3rd ed., Wiley, New York (1999), or P. Kocienski, Protecting Groups,Thieme, Stuttgart (1994)).

Step 22: Process for Preparation of Compound [1-d] (R is a Group whichReproduces carboxyl Group by hydrolysis in Vivo)

Compound [1-d] (R is a group which reproduces carboxyl group byhydrolysis in vivo) is prepared by introducing using a conventionalmethod, a group which reproduces carboxyl group by hydrolysis in vivointo carbapenem compound [1-d] (R is hydrogen atom). For example,carbapenem compound [1-d] (R is hydrogen atom) or its carboxylic acidsalt is reacted with various halides of the compound 10, if necessary,in the presence of a base such as diisopropylethylamine, triethylamine,4-dimethylaminopyridine, potassium carbonate or sodiumhydrogencarbonate, or phase transfer catalyst such astriethylbenzylammoniun chloride or tetrabutylammonium bromide. Thereaction solvent is not limited as far as it is inert and it includespreferably dimethylformamide, dimethyl sulfoxide,hexamethylphosphoramide, acetonitrile, dioxane or tetrahydrofuranoracetone. The carboxylic acid salt includes preferably its sodium orpotassium salt. The reaction is carried out at −78° C. to 100° C.,preferably −20° C. to 60° C. Furthermore, in step 16, using compound 5Aor 5B having a group which reproduces carboxyl group by hydrolysis invivo in R⁸, and then, via each step, carbapenem compound [1-d] (R is agroup which reproduces carboxyl group by hydrolysis in vivo) can bedirectly prepared.

In the above steps, after reaction the product is isolated by the methodaccording to organic chemistry, and when the product is water soluble,the reaction mixture is adjusted to around neutralization and issubjected to column chromatography using absorption resin, etc. Thefractions containing the object compound are taken and lyophilized togive the object compound.

The optical isomers based on asymmetric carbon atoms on the presentcarbapenem compound at 5- and 6-positions of7-oxo-1-azabicyclo[3.2.0]hept-2-ene, a core structure, exist as shown ina following formula [5],

These isomers are all conveniently expressed by only one formula, butthe scope of the present invention should not be construed to be limitedthereto, and includes all isomers and a mixture of isomers based on eachasymmetric carbon atom. The preferable isomers are ones wherein the5-carbon atom has an R-configuration such as (5R, 6R)-compounds or (5R,6S)-compounds. More preferable compounds are one represented by afollowing formula [5a],

Furthermore, when R¹ is 1-hydroxyethyl group, there are isomers havingan R-configuration and an S-configuration at position 8 as shown in afollowing formula [5b], and an isomer having the R-configuration ispreferable.

The isomers having (5R,6S,8R)-configuration of the following formula[5C]:

are most preferable.

In regard to the substitution position on benzene ring which is, a sidechain at position 3, said substitution position is not limited, and metaor para position is preferable.

Examples of carbapenem compound of the present invention are illustratedas compounds 1 to 176 in Tables 1 to 20.

TABLE 1

Compound number R 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 2

Compound number R 17

18 —CH₂OAc 19

20

21

22

23

24

25

26

27

28

29

30

31

32 —H

TABLE 3

Compound number R A 33 —CH₂OCOt-Bu

34 —CH₂OAc

35

36

37

38

39

40 —CH₂OCOt-Bu

TABLE 4

Compound number R A 41 —CH₂OCOt-Bu

42 —CH₂OAc

43

44

45

46

47

48 —CH₂OCOt-Bu

TABLE 5

Compound number R A 49 —CH₂OCOt-Bu

50 —CH₂OAc

51

52

53

54 —CH₂OCOt-Bu

55

56

TABLE 6

Compound number R A 57 —H

58 —H

59 —H

60 —H

61 —H

62 —H

63 —H

64 —H

TABLE 7

Compound number R A 65 —CH₂OCOt-Bu

66 —CH₂OAc

67

68

69

70 —CH₂OCOt-Bu

71

72 —CH₂OCOt-Bu

TABLE 8

Compound number R A 73 —H

74 —H

75 —H

76 —H

77 —H

78 —H

79 —H

80 —H

TABLE 9

Compound number R A 81 —CH₂OCOt-Bu

82 —CH₂OAc

83

84

85

86

87

88

TABLE 10

Com- pound number R A 89 —H

90 —H

91 —H

92 —H

93 —H

94 —H

95 —H

96 —H

TABLE 11

Compound number R A 97 —CH₂OCOt-Bu

98 —CH₂OCOCHMe₂

99

100

101

102

103

104

TABLE 12

Com- pound number R A 105 —H

106 —H

107 —H

108 —H

109 —H

110 —H

111 —H

112 —H

TABLE 13

Compound number R A 113 —CH₂OCOt-Bu

114 —CH₂OCOCHMe₂

115

116

117

118

119

120

TABLE 14

Compound number R A 121 —H

122 —H

123 —H

124 —H

125 —H

126 —H

127 —H

128 —H

TABLE 15

Compound number R A 129 —CH₂OCOt-Bu

130 —CH₂OAc

131

132

133

134 —CH₂OCOt-Bu

135

136 —CH₂OCOt-Bu

TABLE 16

Compound number R A 137 —H

138 —H

139 —H

140 —H

141 —H

142 —H

143 —H

144 —H

TABLE 17

Compound number R A 145 —CH₂OCOt-Bu

146 —CH₂OAc

147

148

149

150

151

152

TABLE 18

Compound number R A 153 —H

154 —H

155 —H

156 —H

157 —H

158 —H

159 —H

160 —H

TABLE 19

Compound number R A 161 —CH₂OCOt-Bu

162 —CH₂OCOCHMe₂

163

164

165

166

167

168

TABLE 20

Compound number R A 169 —H

170 —H

171 —H

172 —H

173 —H

174 —H

175 —H

176 —H

The compounds illustrated above have stereoisomers as described above orelse stereoisomers based on asymmetric carbon atoms, and the compoundsinclude all these isomers.

EXAMPLE

The present invention is explained by the following examples, but thepresent invention is not limited to these examples

Abbreviations Used in the Following Examples Means Below.

-   Ac: acetyl group-   AOC: allyloxycarbonyl group-   t-Bu: tert-butyl group-   DMF: N,N-dimethylformamide-   DMSO: dimethy sulfoxide-   Et: ethyl group-   Me: methyl group-   MOPS: 4-morpholine propanesulfinic acid-   Ph: phenyl group-   PNB: p-nitrobenzyl group-   TBDMS: tert-butyl(dimethyl) silyl group-   THF: tetrahydrofuran-   TMS: trimethylsilyl group-   ATR: total reflection-absorption method-   br: broad

Reference Example 1

To m-methoxyacetophenone (7.5 g, 50 mmol) and triethylamine (10.5 ml, 75mmol) in dichloromethane (200 ml) was dropped at 0° C. under stirringtrifluoromethanesulfonic acid trimethylsilyl ester (10.9 ml, 60 mmol)and the mixture was stirred at room temperature for 1 hour. To thereaction mixture was added at room temperature(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (14.4 g, 50 mmol) and zinc iodide (9.6 g, 30 mmol), and themixture was stirred for 2 hours. To the reaction mixture was added a 5%aqueous potassium hydrogensulfate solution (250 ml), and an organiclayer was separated by a separatory funnel. An aqueous layer wasextracted with chloroform (100 ml×twice). The extract was combined withthe organic layer, dried over magnesium sulfate, filtered andconcentrated. The residue was purified with silica gel chromatography(silica gel 400 g, hexane:ethyl acetate=2:1˜0:1) to give(3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[2-(3-methoxyphenyl)-2-oxoethyl]azetidin-2-one(15.91 g, yield 84%) as a pale yellowish solid.

¹H NMR (400 MHz, CDCl₃) δ 0.079 (s, 3 H), 0.086 (s, 3 H), 0.88 (s, 9 H),1.26 (d, 3 H, J=6.2 Hz), 2.89 (dd, 1 H, J=5.3, 2.2 Hz), 3.16 (dd, 1 H,J=17.7, 10.2 Hz), 3.45 (dd, 1 H, J=17.7, 3.0 Hz), 3.87 (s, 3 H),4.10-4.15 (m, 1 H), 4.20-4.26 (m, 1 H), 6.11 (br s, 1 H), 7.15 (ddd, 1H, J=8.0, 2.6, 0.9 Hz), 7.40 (t, 1 H, J=8.0 Hz), 7.47 (dd, 1 H, J=2.6,1.6 Hz), 7.51-7.53 (m, 1 H).

Reference Example 2

(3S,4R)-3-((1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-[2-(3-methoxyphenyl)-2-oxoethyl]azetidin-2-oneobtained in Reference example 1 (15.67 g, 41.5 mmol) and allylglyoxalate monohydrate (7.14 g, 54 mmol) were dissolved in toluene (400ml), and the mixture was refluxed for 8 hours while excluding resultingwater with Dean Stark trap. The reaction solution was concentrated. Theresidue and 2,6-lutidine (6.67 g, 62.3 mmol) was dissolved in THF (200ml). Thereto was dropped at −20° C. thionyl chloride (7.4 g, 62.3 mmol)and the mixture was stirred for 30 minutes, followed by stirring for 30minutes at room temperature. To the reaction mixture was added THF (200ml), the insoluble materials were filtered under an atmosphere ofnitrogen, and washed with THF. The filtrate and the washed solution werecombined and concentrated. The residue was dissolved in 1,4-dioxane (600ml), and thereto were added 2,6-lutidine (9.8 g, 91.3 mmol) andtriphenylphosphine (24.0 g, 91.3 mol), followed by stirring at 60° C.for 4 hours. After cooling, the reaction mixture was concentrated, andethyl acetate (500 ml) was added to the residue. The mixture was washedwith brine (100 ml×3 times), dried over magnesium sulfate, andconcentrated. The residue was purified with silica gel columnchromatography (silica gel 500 g, hexane:ethyl acetate=2:1˜1:1) to giveallyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(23.8 g, yield 78%) as a yellow amorphous.

Reference Example 3

Allyl{(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(3.0 g) prepared by Reference example 2 was dissolved at roomtemperature in a 70% aqueous trifluoroacetic acid solution (10 ml). Tothe reaction mixture was added ethyl acetate (100 ml) and the mixturewas washed with saturated brine (100 ml×twice), and a saturatedhydrogencarbonate solution (100 ml×twice), dried over magnesium sulfate,filtered, and concentrated to give allyl{(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilidene)acetate(3.09 g) as a pale yellow amorphous. This product was subjected to nextreaction without further purification.

Step b)

Allyl{(2R,3S)-3-[(1R)-1-hydroxyethyl]-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxoazetidin-1-yl}(triphenylphosphoranilldene)acetate(3.09 g) prepared by step a) and triethylamine (0.86 ml, 6.12 mmol) weredissolved in THF (15 ml), and thereto was added at 0° C.chlorotrimethylsilane (0.62 ml, 4.9 mmol), followed by stirring for 30minutes. Triethylamine (0.86 ml, 6.12 mmol) and chlorotrimethylsilane(0.62 ml, 4.9 mmol) were further added thereto and the mixture wasstirred for 20 minutes. To the reaction mixture was added ethyl acetate,and the mixture was washed with aqueous saturated hydrogencarbonatesolution/saturated brine (1:1, 50 ml×twice), and saturated brine (100ml), dried over magnesium sulfate, filtrated, and concentrated to giveallyl((2R,3S)-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilidene)acetate(3.26 g) as a yellow oil. This product was subjected to next reactionwithout further purification.

Step c)

Allyl((2R,3S)-2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-1-yl)(triphenylphosphoranilldene)acetateprepared by step b) was dissolved in xylene (100 ml), and thereto wasadded N,O-bistrimethylsilylacetoamide (1.0 ml), followed by refluxingfor 4 hours. After cooling the reaction mixture was concentrated, andthe residue was purified with column chromatography (silica gel 100 g,chloroform:methanol=100:0˜100:3) to give allyl(5R,6S)-3-(3-methoxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.70 g, quantatively) as a pale yellow oil.

LC/MS (EI) 416 (M+1), 344 (M+1-TMS).

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9 H), 1.30 (d, 3 H, J=6.2 Hz),3.13-3.31 (m, 3 H), 3.80 (s, 3 H), 4.19-4.24 (m, 2 H), 4.60-4.66 (m, 1H), 4.69-4.74 (m, 1 H), 5.16-5.19 (m, 1 H), 5.24-5.29 (m, 1 H),5.81-5.90 (m, 1 H), 6.86-6.93 (m, 3 H), 7.24-7.28 (m, 1 H).

Step d)

Allyl(5R,6S)-3-(3-methoxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.70 g, 4.09 mmol) prepared by step c) was dissolved in THF (40 ml) andwater (20 ml), and the mixture was cooled in a water bath and theretowas gradually dropped 1N hydrochloric acid using a pH meter so as tobecome pH=2.5. After 15 minutes, thereto were added an aqueous saturatedsodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml),and the mixture was extracted with chloroform (50 ml×3 times). Theorganic layers were combined and dried over magnesium sulfate, filtered,and concentrated to give allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.37 g, 3.99 mmol, yield 98%) as a pale yellow oil.

LC/MS (EI) 344 (M+1).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3 H, J=6.3 Hz), 1.63 (br s, 1 H),3.17-3.33 (m, 3 H), 3.80 (s, 3 H), 4.23-4.33 (m, 2 H), 4.60-4.66 (m, 1H), 4.69-4.75 (m, 1 H), 5.16-5.20 (m, 1 H), 5.23-5.28 (m, 1 H),5.80-5.90 (m, 1 H), 6.87-6.94 (m, 3 H), 7.25-7.29 (m, 1 H).

Reference Example 4

To a 20% ethanol solution containing sodium ethoxide (68.7 g) wasdropped at 4˜50° C. under stirring diethyl malonate (32.4 g), followedby stirring for 10 minutes. To the mixture was added at room temperature4-chloro-3-nitroacetophenone (20.2 g) and the mixture was stirred for 3hours. To the reaction mixture were added 2N hydrochloric acid (200 mL)and chloroform (200 mL), and the organic layer was separated. Theaqueous layer was extracted with chloroform (2×100 mL), and the organiclayers were combined, dried over magnesium sulfate, filtered, and thesolvent was evaporated in vacuo to give a mixture of the object compoundand diethyl malonate (54.1 g, quantitatively). The mixture was subjectedto next reaction without further purification.

The sample for analysis was purified with silica gel columnchromatography (hexane/ethyl acetate).

¹H NMR (400 MHz, CDCl₃) δ 1.29 (t, 6 H,. J=7.1 Hz), 2.67 (s, 3 H), 4.280(q, 2 H, J=7.1 Hz), 4.283 (q, 2 H, J=7.1 Hz), 5.33 (s, 1 H), 7.67 (d, 1H, J=8.1 Hz), 8.20 (dd, 1 H, J=8.1, 1.8 Hz), 8.60 (d, 1 H, J=1.8 Hz).

Step b)

(4-Acetyl-2-nitrophenyl)acetic acid

A mixture of diethyl(4-acetyl-2-nitrophenyl)malonate and diethylmalonate (54.1 g) prepared by step a) was dissolved in 4M HCl (800mL)/dioxane (800 mL), and the solution was stirred at 100° C. for 8hours. After cooling, dioxane was removed in vacuo, and the aqueouslayer was extracted with chloroform (200 mL×1, 100 mL×2). The organiclayers were combined, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo to give the object compound (23.1 g,quantitatively) as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ 2.68 (s, 3 H), 4.14 (s, 2 H), 7.50 (d, 1 H,J=7.9 Hz), 8.18 (dd, 1 H, J=1.7, 7.9 Hz), 8.68 (d, 1 H, J=1.7 Hz).

Step c)

Ethyl (4-acetyl-2-nitrophenyl)acetate

(4-Acetyl-2-nitrophenyl)acetic acid (23.1 g) prepared by step b) wasdissolved in ethanol (500 mL) and thereto was added concentratedhydrochloric acid (50 mL), followed by refluxing for 6 hours. Aftercooling, ethanol was removed in vacuo, and to the aqueous layer wereadded ethyl acetate (300 mL) and a saturated sodium hydrogencarbonatesolution (100 mL). The mixture was neutralized with addition of sodiumhydrogencarbonate powder. The aqueous layer was separated and theorganic layer was washed with a saturated sodium hydrogencarbonatesolution (100 mL) and saturated brine (100 mL), dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. The residue waspurified with column chromatography (SiO₂ 100 g, hexane/ethyl acetate1:1) to give the object compound (23.2 g,91%) as a brown oil. Theaqueous layer was acidified with hydrochloric acid and extracted withchloroform to recover (4-acetyl-2-nitrophenyl)acetic acid (1.8 g, 8%).

¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, 3 H, J=7.1 Hz), 2.67 (s, 3 H), 4.09(s, 2 H), 4.18 (q, 2 H, J=7.1 Hz), 7.49 (d, 1 H, J=7.9 Hz), 8.16 (dd, 1H, J=1.8, 7.9 Hz), 8.65 (d, 1 H, J=1.8 Hz). LCMS (EI) 252 (M+1)+.

Step d)

A mixture of ethyl (4-acetyl-2-aminophenyl)acetate and ethyl[2-amino-4-(1-hydroxyethyl)phenyl]acetate

Ethyl (4-acetyl-2-nitrophenyl)acetate (23.2 g) prepared by step c) wasdissolved in ethanol (660 mL) and thereto was added Pd—C (5%, 5.9 g).The mixture was stirred at ordinary pressure under an atmosphere ofhydrogen for 9.5 hours. Pd—C was filtered off with Celite, and thesolvent was removed in vacuo to give the object compound (20.4 g,quantitatively) as a brown oil. Ratio of the ketone compound and thealcohol compound was 1:2 by NMR analysis. This product was subjected tonext reaction without further purification.

LCMS (EI) 222 (M+1)+ketone, 224 (M+1)+alcohol.

Step e)

Ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate and ethyl[2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate

A mixture of ethyl (4-acetyl-2-aminophenyl)acetate and ethyl[2-amino-4-(1-hydroxyethyl)phenyl]acetate (20.4 g) prepared by step d)was dissolved in pyridine (184 mL) and thereto was dropped at roomtemperature allyloxycarbonyl chloride (22.2 g), followed by stirring for30 minutes. To the reaction mixture were added a saturated ammoniumchloride solution (100 mL) and saturated brine (100 mL), and thenpyridine was removed in vacuo. To the aqueous layer was added 2Mhydrochloric acid (200 mL) and the mixture was extracted with ethylacetate (3×100 mL). The organic layers were combined, washed with 2Mhydrochloric acid (3×50 mL) and saturated brine (50 mL), filtered andthe solvent was removed in vacuo. The residue was purified with columnchromatography (SiO₂ 500 g, hexane/ethyl acetate 3:1˜1:1) to give ethyl(4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate (7.34 g, 26%) as agray oil, and ethyl[2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate (14.1 g,50%) as a purple oil.

Ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, 3 H, J=7.1 Hz), 2.60 (s, 3 H), 3.68(s, 2 H), 4.18 (q, 2 H, J=7.1 Hz), 4.69-4.71 (m, 2 H), 5.26-5.30 (m, 1H), 5.37-5.41 (m, 1 H), 5.95-6.05 (m, 1 H), 7.30 (d, 1 H, J=8.0 Hz),7.69 (dd, 1 H, J=1.8, 8.0 Hz), 8.12 (bs, 1 H), 8.42 (bs, 1 H). LCMS (EI)306 (M+1)+.

Ethyl [2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, 3 H, J=7.1 Hz), 1.49 (d, 3 H, J=6.4Hz), 3.61 (s, 2 H), 4.16 (q, 2 H, J=7.1 Hz), 4.67-4.69 (m, 2 H), 4.89(q, 1 H, J=6.4 Hz), 5.24-5.28 (m, 1 H), 5.34-5.40 (m, 1 H), 5.94-6.03(m, 1 H), 7.12 (dd, 1 H, J=1.7, 7.8 Hz), 7.18 (d, 1 H, J=7.8 Hz), 7.81(bs, 1 H), 8.07 (bs, 1 H). LCMS (EI) 308 (M+1)+.

Step f)

Ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate

Ethyl [2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate(10.3 g) prepared by step e) was dissolved in acetone (30 mL) andthereto was added at room temperature Jons' reagent (10 mL), followed bystirring for 30 minutes. To the reaction solution were added saturatedbicarbonate solution (50 mL) and saturated brine (100 mL), and themixture was extracted with ethyl acetate (3×50 mL). The organic layerwas combined, dried over magnesium sulfate, filtered and the solvent wasremoved in vacuo to give a crude product. The crude product was combinedwith the crude product prepared separately prepared in a scale of 1 gand purified with column chromatography (SiO₂ 300 g, hexane/ethylacetate 1:1) to give the object compound (10.3 g, 85%) as a yellow oil.

Step g)

(4-Acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetic acid

Ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate (17.6 g)prepared by step e) and step f) was dissolved in ethanol (176 mL) andthereto was added at 0° C. 1M aqueous NaOH solution (132 mL), followedby stirring for 1 hour. To the reaction solution was added 2Mhydrochloric acid (400 mL), and ethanol was removed in vacuo. Theresulting solid was collected by filtration and washed with 2Mhydrochloric acid, and dried in vacuo to give the object compound as apale brown solid (11.2 g, 70%). Further the aqueous layer was extractedwith ethyl acetate, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo to give the object compound (3.58 g, 22%)as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ 2.59 (s, 3 H), 3.74 (s, 2 H), 4.68-4.70 (m, 2H), 5.27 (bd, 1 H, J=10.8 Hz), 5.35 (bd, 1 H, J=15.3 Hz), 5.60 (bs, 1H), 7.34 (d, 1 H, J=7.9 Hz), 7.70 (bs, 1 H), 7.74 (dd, 1 H, J=1.5, 7.9Hz), 8.25 (bs, 1 H).

Step h)

4-Nitrobenzyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate

To (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetic acid (10.9 g)prepared by step g) and triethylamine (11 mL) in DMF (100 mL) was addedat room temperature p-nitrobenzyl bromide (17.0 g), and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture wereadded saturated brine (500 mL) and water (300 mL), and the mixture wasextracted with ethyl acetate (200 mL, 2×100 mL). The organic layers werecombined, washed with saturated brine (100 mL), dried over magnesiumsulfate, filtered and the solvent was removed in vacuo. The residue waspurified with column chromatography (SiO₂ 300 g, hexane/ethylacetate/chloroform=3:1:4˜0:1:1) to give the object compound (16.4 g,98%) as a pale brown solid. Further the product was recrystallized fromchloroform/hexane to give the object compound (10.4 g, 64%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 2.61 (s, 3 H), 3.78 (s, 2 H), 4.68-4.70 (m, 2H), 5.24 (s, 2 H), 5.27-5.30 (m, 1 H), 5.35-5.40 (m, 1 H), 5.93-6.01 (m,1 H), 7.32 (d, 1 H, J=8.0 Hz), 7.46-7.50 (m, 2 H), 7.71 (dd, 1 H, J=1.8,8.0 Hz), 7.73 (bs, 1 H), 8.22 (td, 2 H, J=2.3, 6.8 Hz), 8.38 (bs, 1 H).LCMS (EI) 413 (M+1)+.

Step i)

4-Nitrobenzyl(2-{[(allyloxy)carbonyl]amino}-4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)acetate

To 4-nitrobenzyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate(10.0 g) and triethylamine (8.2 mL) in dichloromethane (100 mL) wasdropped at 0° C. trifluoromethanesulfonic acid trimethylsilyl ester(11.9 g). After detecting the production of silylenol ether by TLC,(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (6.98 g) and zinc iodide (4.65 g) were added thereto at 0° C.After stirring for 1 hour, further(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (3.0 g) was added thereto and the mixture was stirred at roomtemperature for 14 hours. To the reaction mixture were added a 5%aqueous potassium hydrogensulfate solution (380 mL) and saturated brine(100 mL), and the mixture was extracted with ethyl acetate (200 mL,2×100 mL). The organic layers were combined, dried over magnesiumsulfate, filtered and the solvent was removed in vacuo. The residue waspurified with column chromatography (SiO₂ 500 g, hexane/ethyl acetate1:1˜1:3) to give the object compound (11.4 g, 70%) as a pale amorphous.

¹H NMR (400 MHz, CDCl₃) δ 0.08 (s, 3 H), 0.08 (s, 3 H), 0.88 (s, 9 H),1.25 (d, 3 H, J=6.2 Hz), 2.90 (dd, 1 H, J=2.2, 5.1 Hz), 3.18 (dd, 1 H,J=10.1, 17.8 Hz), 3.45 (dd, 1 H, J=3.0, 17.8 Hz), 3.79 (s, 2 H),4.10-4.15 (m, 1 H), 4.20-4.26 (m, 1 H), 4.69 (td, 2 H, J=1.4, 4.4 Hz),5.25 (s, 2 H), 5.27-5.31 (m, 1 H), 5.35-5.40 (m, 1 H), 5.93-6.03 (m, 1H), 6.12 (bs, 1 H), 7.34 (d, 1 H, J=8.0 Hz), 7.47-7.50 (m, 2 H), 7.70(dd, 1 H, J=1.8, 8.0 Hz), 7.83 (bs, 1 H), 8.21-8.24 (m, 2 H), 8.39 (bs,1 H). LCMS (EI) 640 (M+1)+.

Step j)

Allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}-4-{2-[(4-nitrobenzyl)oxy]-2-oxoethyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate

4-Nitrobenzyl(2-{[(allyloxy)carbonyl]amino}-4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)acetate(11.4 g) prepared by step i) was treated in the same method as Referenceexample 2 to give the object compound (10.4 g, 59%) as a pale brownamorphous.

LCMS (EI) 998 (M+1)+.

Step k)

(2-{[(Allyloxy)carbonyl]amino}-4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranihdene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid

Allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}-4-{2-[(4-nitrobenzyl)oxy]-2-oxoethyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(10.4 g) prepared by step j) was dissolved in THF (200 mL) and theretowas added zinc (3.4 g) to give a suspension. Further thereto was addedat room temperature 2M ammonium chloride solution (26 mL) and themixture was stirred for 2 hours. Thereto was added acetic acid (6.3 g)and the mixture was stirred for further 1 hour. To the reaction mixturewas added a 5% aqueous potassium hydrogensulfate solution (200 mL) andthe mixture was extracted with ethyl acetate (3×100 mL). The extractswere combined, washed with a 5% aqueous potassium hydrogensulfatesolution (100 mL), dried over magnesium sulfate, filtered and thesolvent was removed in vacuo. The residue was purified with columnchromatography (SiO₂ 300 g, chloroform/methanol 98:2˜90:10) to give theobject compound (9.11 g, quantitatively) as a reddish brown amorphous.

LCMS (EI) 863 (M+1)+.

Step l)

Allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}-4-{2-oxo-2-[(pyridine4-ylmethyl)amino]ethyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate

2-{[(Allyloxy)carbonyl]amino}-4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)aceticacid (1.5 g) prepared by step k) and 4-picolylamine (0.67 g) weredissolved in THF (15 mL) and thereto was added WSCI.HCl (0.38 g),followed by stirring for 30 minutes. Further WSCI.HCl (0.38 g) was addedthereto and the mixture was stirred for 14 hours. To the reactionmixture was added saturated brine (50 mL) and the mixture was extractedwith chloroform (3×50 mL). The organic layers were combined, dried overmagnesium sulfate, filtered and the solvent was removed in vacuo to givea crude product (2.92 g, quantitatively).

LCMS (EI) 953 (M+1)+.

Step m)

Allyl(5R,6S)-3-(3-{[(allyloxy)carbonyl]amino}-4-{2-oxo-2-[(pyridin-4-ylmethyl)amino]ethyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Allyl[(2R,3S)-2-[2-(3-{[(allyloxy)carbonyl]amino}-4-{2-oxo-2-[(pyridin-4-ylmethyl)amino]ethyl}phenyl)-2-oxoethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-1-yl](triphenylphosphoranilidene)acetate(2.9 g) prepared by step l) was treated in the same method asReferential example 3 to give the object compound (0.58 g) as a brownamorphous. Although this product contained triphenylphosphinoxide, theproduct was subjected to next reaction without further purification.

Reference Example 5 2-(4-Acetyl-2-chlorophenyl)ethyl acetate

2-Chlorophenethyl alcohol (10 g) was dissolved in hexane (300 ml) andthereto was added aluminum chloride (28.1 g). Under ice cooling, acetylchloride (15.0 g) was dropped thereto. After 1 hour, the reactionmixture was added in ice water, then extracted with ethyl acetate, andwashed with brine. The organic layer was dried, concentrated and theresidue was purified with silica gel column chromatography(hexane:acetic acidethyl=3:1) to give the object compound (4.47 g).

¹H NMR (400 MHz, CDCl₃) δ 2.03 (s, 3H), 2.59 (s, 3H), 3.13 (t, 2H, J=6.8Hz), 4.33 (t, 2H, J=6.8 Hz), 7.46 (d, 1H, J=8.3 Hz), 7.76 (dd, 1H,J=8.3, 2.2 Hz), 7.85 (d, 1H, J=2.2 Hz)

Reference Example 6 1-[3-Chloro-4-(2-hydroxyethyl)phenyl]ethanone

2-(4-Acetyl-2-chlorophenyl)ethyl acetate (4.87 g) was dissolved inmethanol (80 ml), and thereto was added concentrated hydrochloric acid(20 ml), followed by refluxing. Four hours later the temperature of thereaction mixture was kept at room temperature, and methanol was removedin vacuo. Then the residue was diluted with ethyl acetate, washed withbrine, dried and concentrated to give the object compound (4.42 g).

¹H NMR (400 MHz, CDCl₃) δ 2.59 (s, 3H), 3.08 (t, 2H, J=6.6 Hz), 3.93 (t,2H, J=6.8 Hz), 7.46 (d, 1H, J=8.3 Hz), 7.76 (dd, 1H, J=8.3, 2.2 Hz),7.89 (d, 1H, J=2.2 Hz)

Reference Example 7 4-Acetyl-2-cchlorophenylacetic acid

1-[3-Chloro-4-(2-hydroxyethyl)phenyl]ethanone (4.42 g) was dissolved inacetone (50 ml), and thereto was added Jones reagent (13 ml). Thereaction mixture was diluted with ethyl acetate, washed with brine,dried, and concentrated. The residue was purified with silica gel columnchromatography (chloroform:methanol=25:1) to give the object compound(2.65 g).

¹H NMR (400 MHz, CDCl₃) δ 2.59 (s, 3H), 3.89 (s, 2H), 7.51 (d, 1H, J=8.3Hz), 7.84 (d, 1H, J=8.3 Hz), 7.90 (s, 1H)

Reference Example 8

To 4-acetyl-2-chlorophenylacetic acid (2.65 g, 12.5 mmol) in DMFsolution (26 mL) were added triethylamine (3.5 ml, 25 mmol) and4-nitrobenzyl bromide (5.4 g, 25mol), and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was added to anice cooled saturated potassium hydrogencarbonate solution, the organiclayer was separated by a separatory funnel, and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined and driedover sodium sulfate, filtered and concentrated. The residue was purifiedwith silica gel chromatography (silica gel 180 ml, hexane:EtOAc=2:1→1:1)to give 4-nitrobenzyl (4-acetyl-2-chlorophenyl)acetate (3.56 g, yield,82%) as white crystals. The product was subjected to next reactionwithout further purification. To4-nitrobenzyl(4-acetyl-2-chlorophenyl)acetate (3.56 g, 11.4 mmol) andtriethylamine (2.0 ml, 15.9 mmol) in dichloromethane (36 ml) was droppedat 0° C. under stirring trifluoromethanesulfonic acid trimethylsilylether (2.4 ml, 14.8 mmol), and the mixture was stirred for 20 minutes.To the reaction mixture were added at 0° C. dichloromethane (50 mL),(2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinylacetate (4.6 g, 15.9 mmol), and zinc iodide (2.2 g, 6.8 mmol), and thenthe ice bath was removed. The mixture was stirred at room temperaturefor 4.5 hours and then added to an ice cooled saturated potassiumhydrogencarbonate solution. The organic layer was separated by aseparatory funnel and the aqueous layer was extracted with ethylacetate. The organic layers were combined, dried over sodium sulfate,filtered, and concentrated. The residue was purified with silica gelchromatography (silica gel 180 ml, hexane:EtOAc=4:1→0:1) to give4-nitrobenzyl(4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)acetate(5.2 g, yield 79.7%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 0.079 (s, 6 H), 0.88 (s, 9 H), 1.26 (d, 3 H,J=6.2 Hz), 2.88 (dd, 1 H, J=5.2, 2.4 Hz), 3.14 (dd, 1 H, J=18, 10 Hz),3.43 (dd, 1 H, J=17.6, 2.8 Hz), 3.92 (s, 2 H), 4.09-4.12 (m, 1 H),4.21-4.23 (m, 1 H), 5.26 (s, 2 H), 6.06 (br-s, 1 H), 7.50-7.54 (m, 3 H),7.82 (dd, 1 H, J=8.4, 2.0 Hz), 7.89 (d, 1 H, J=2.0 Hz), 8.22 (dd, 2 H,J=6.8, 4.8 Hz).

Reference Example 9

4-Nitrobenzyl(4-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)acetate(5.2 g, 9.6 mmol) prepared by Reference example 8 and allyl glyoxalatemonohydrate (1.8 g, 13.6 mmol) were dissolved in toluene (105 ml), andthe mixture was refluxed for 4 hours while eliminating the resultedwater with Dean Stark trap. The reaction solution was concentrated, andthe residue and 2,6-lutidine (1.9 mL, 16.3 mmol) were dissolved in THF(101 ml). At between −20° C. to −30° C., thionyl chloride (0.93 mL, 12.7mmol) was dropped thereto and stirred for 12 minutes. The insolublematerials were filtered off under an atmosphere of nitrogen, washed withTHF, and the filtrate was combined with the washed solution, followed byconcentration. The residue was dissolved in 1,4-dioxane (108 ml) andthereto were added triphenylphosphine (5.2 g, 19.9 mmol) and2,6-lutidine (2.4 mL, 20.8 mmol). The mixture was stirred at 40° C. for6 hours. After cooling, the reaction solution was concentrated, and tothe residue was added ethyl acetate. The mixture was washed with brine,dried over magnesium sulfate, and concentrated. The residue was purifiedwith silica gel column chromatography (silica gel 180 mL, hexane/ethylacetate=2:1→1:2) to give allyl{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-chloro-4-{2-[(4-nitrobenzyl)oxy]-2-oxoethyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl]}(triphenylphosphoranilidene)acetate(5.4 g, yield 64%) as a pale yellow amorphous.

LC/MS (EI) 933 (M+1)

Reference Example 10

Allyl {[(2R,3 S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-chloro-4-{2-[(4-nitrobenzyl)oxy]-2-oxoethyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl]}(triphenylphosphoraniliden)acetate(2.0 g, 2.1 mmol) prepared by Reference example 9 was dissolved in THF(40 mL), and thereto were added zinc powder 2.1 g (31.5 mol), ammoniumchloride solution (2M, 16 mL, 31.5 mmol), and acetic acid (1.8 mL, 31.5mmol), and the mixture was stirred at room temperature for 5 hours. Thereaction mixture was filtered with Celite (washed with ethyl acetate),and the filtrate was washed with a 5% aqueous potassium hydrogensulfatesolution and saturated brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified silica gel column chromatography(silica gel 60 mL, chloroform/methanol=1:0→25:1) to give(4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)aceticacid (1.7 g, yield, 98%) as a pale yellow amorphous.

LC/MS (EI) 799 (M+1)

Step b)

(4-{[(2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}-2-chlorophenyl)aceticacid (1.4 g, 1.75 mmol) prepared by step a), was added to4-aminomethylimidazole dihydrate (0.51 g, 3.0 mmol) and triethylamine(0.83 ml, 6.0 mmol) in an ice cooled DMF (20 mL), and then thereto wereadded 1-hydroxybenzotriazole (0.47 g, 3.5 mmol) and EDCI (0.67 g, 3.5mmol), followed by stirring for 5 minutes. After removal of the icebath, the mixture was stirred for 150 minutes. To the reaction mixturewere added ice water and ethyl acetate. The mixture was washed withwater and saturated brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified with silica gel columnchromatography (silica gel 60 mL, chloroform/methanol=1:0→10:1→5:1) togive allyl{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-chloro-4-{2-[(1H-imidazol-5-ylmethyl)amino]-2-oxoethyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl]}(triphenylphosphoranilidene)acetate(1.3 g, yield, 84%) as a pale yellow amorphous. This product wassubjected to next reaction without further purification. Allyl{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[2-(3-chloro-4-{2-[(1H-imidazol-5-ylmethyl)amino]-2-oxoethyl}phenyl)-2-oxoethyl]-4-oxoazetidin-1-yl]}(triphenylphosphoranilidene)acetate(1.29 g) and 4-dimethylaminopyridine (18 mg, 0.14 mmol) were dissolvedin pyridine (13 ml), and thereto was added at 0° C. allyl chloroformate(0.2 ml, 1.9 mmol), followed by stirring for 20 minutes. To the reactionsolution was added ethyl acetate. The mixture was washed with saturatedbicarbonate solution and saturated brine, dried over sodium sulfate,filtered, and concentrated to give an yellow oil (1.35 g). This productwas dissolved in a cooled 70% TFA solution (10 ml), and the mixture wasstirred for 5 minutes. After removal of the ice bath, the mixture wasstirred for 30 minutes, and again cooled in the ice bath. To thereaction solution was added saturated biscarbonate solution to adjust pHof the medium to 8.0 and then thereto was added ethyl acetate. Themixture was washed with saturated brine, dried over sodium sulfate,filtered, and concentrated to give a pale yellow amorphous (1.2 g). Thisproduct was subjected to next reaction without further purification.Thus obtained pale yellow amorphous (1.2 g) and triethylamine (1.56 ml,11.2 mmol) were dissolved in THF (24 ml), and to the solution was addedat 0° C. chlorotrimethylsilane (1.52 ml, 8.4 mmol), followed by stirringfor 5 minutes. After removal of the ice bath, the mixture was stirred atroom temperature for 25 minutes and again cooled in an ice bath. To thereaction mixture were added ethyl acetate and saturated bicarbonatesolution. The organic layer was washed with saturated brine, dried oversodium sulfate, filtered and concentrated to give allyl5-{[({4-[((2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-2-yl)acetyl]-2-chlorophenyl}acetyl)amino]methyl}-1H-imidazole-1-carboxylate(1.27 g, yield 83%) as an yellow oil.

LC/MS (EI) 919 (M+1)

Step c)

Allyl5-{[({4-[((2R,3S)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranilidene)ethyl]-4-oxo-3-{(1R)-1-[(trimethylsilyl)oxy]ethyl}azetidin-2-yl)acetyl]-2-chlorophenyl}acetyl)amino]methyl}-1H-imidazole-1-carboxylate(1.27 g) prepared by step c) was dissolved in toluene (26 ml), andthereto were added N,O-bistrimethylsilylacetamide (0.7 ml) and2,6-di-tert-butyl p-cresol (20 mg), followed by refluxing at 100° C. for2 hours. After cooling, the reaction solution was concentrated, and theresidue was purified with column chromatography (silica gel 150 mL,chloroform:methanol=100:0˜100:3) to give allyl(5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.78 g, yield 89%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9 H), 1.29 (d, 3 H, J=6.4 Hz),3.10-3.30 (m, 3 H), 3.69 (s, 2 H), 4.15-4.21 (m, 2 H), 4.35 (d, 2 H,J=5.6 Hz),4.58-4.65 (m, 2 H), 4.85-4.87 (m, 2 H), 5.18-5.46 (m, 4 H),5.81-6.05 (m, 2 H), 6.12-6.20 (m, 1 H), 7.30 (s, 1 H), 7.36-7.70 (m, 3H), 7.45-7.60 (m, 2 H), 8.05 (s, 1 H).

Step d)

Allyl(5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.78 g, 1.22 mmol) prepared by step c) was dissolved in THF (23 ml) andwater (11 ml), and the solution was cooled in a water bath. Thereto wasgradually dropped using a pH meter, 0.1N hydrochloric acid to adjust pHto 3.0. Fifteen minutes later, pH of the solution was adjusted 6.8 bygradually dropping saturated bicarbonate solution thereto, and thensaturated brine (50 ml) was added. The solution was extracted with ethylacetate. The organic layers were combined, dried over sodium sulfate,filtered, and concentrated to give allyl(5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.54 g, yield 78%) as a pale yellow amorphous.

¹H NMR (400 MHz, CDCl₃) δ 1.37 (d, 3 H, J=6.0 Hz), 1.61 (br-s, 1 H),3.13-3.35 (m, 3 H), 3.69 (s, 2 H), 4.20-4.32 (m, 2 H), 4.35 (d, 2 H,J=6.0 Hz), 4.57-4.75 (m, 2 H), 4.86 (d, 2 H, J=4.8 Hz), 5.20-5.50 (m, 4H), 5.80-6.02 (m, 2 H), 6.10-6.20 (m, 1 H), 7.31 (s, 1 H), 7.37-7.40 (m,2 H), 7.45-7.60 (m, 2 H), 8.06 (s, 1 H).

Example 1

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.17 g) was dissolved in dry DMF (1.7 ml) and the solution wasice-cooled. Thereto was gradually dropped pivaloyloxymethyl iodide (0.12g) in dry DMF (1.2 ml) and the mixture was stirred. Thirty minuteslater, ethyl acetate was added thereto and the mixture was washed withbicarbonate solution, water and brine, successively. The organic layerwas dried over sodium sulfate, concentrated and the residue was purifiedwith silica gel column chromatography (hexane:ethyl acetate=1:2˜ethylacetate only) to give[(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.15 g, yield 70%).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.37 (d, 3H, J=6.4 Hz), 1.71 (d,1H, J=5.2 Hz), 3.18-3.32 (m, 3H), 3.82 (s, 3H), 4.23-4.31 (m, 2H), 5.79(d, 1H, J=5.2 Hz), 5.89 (d, 1H, J=5.2 Hz), 6.87 (d, 2H, J=12.0 Hz), 7.36(d, 2H, J=12.0 Hz)

Example 2

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.18 g) in dry DMF (3.6 ml) was ice-cooled, and thereto was addedtriethylbenzylammoniun chloride (0.11 g). To the mixture was graduallydropped bromomethylacetate (0.16 ml) and the mixture was graduallyallowed to room temperature and stirred. Forty minutes later, theretowas added ethyl acetate, and the mixture was washed with bicarbonatesolution, water and brine, successively. The organic layer was driedover sodium sulfate, concentrated and the residue was purified withsilica gel column chromatography (ethyl acetate only) to give(acetyloxy)methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.15 g, yield 48%).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, 3H, J=6.0 Hz), 1.71 (d, 1H, J=4.8Hz), 2.09 (s, 3H), 3.20-3.30 (m, 3H), 3.83 (s, 3H), 4.22-4.31 (m, 2H),5.80 (d, 1H, J=4.8 Hz), 5.87 (d, 1H, J=4.8 Hz), 6.88 (d, 2H, J=7.2 Hz),7.39 (d, 2H, J=7.2 Hz)

Example 3

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.43 g) was dissolved in dry DMF (4.3 ml) and thereto was addedtriethylbenzylammonium chloride (0.25 g). Thereto was dropped1-chloroethylcyclohexylcarbonate (0.62 g) and the mixture was stirredunder heating to 50° C. One hour later, the mixture was cooled to roomtemperature and thereto was added ethyl acetate. The mixture was washedwith bicarbonate solution, water and brine, successively. The organiclayer was dried over sodium sulfate, concentrated, and the residue waspurified with silica gel column chromatography (hexane:ethylacetate=1:2→1:3→ethyl acetate only) to give1-{[(cyclohexyloxy)carbonyl]oxy}ethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.12 g, yield 20%).

¹H NMR (400 MHz, CDCl₃) δ 1.13-1.99 (m, 17H), 3.17-3.31 (m, 3H), 3.82(s, 3H), 4.19-4.26 (m, 2H), 4.60-4.65 (m, 1H), 6.83-6.90 (m, 3H), 7.39(t, 2H, J=8.0 Hz)

Example 4

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.15 g) in dry DMF (2.0 ml) was ice-cooled. After4-bromomethyl-5-methyl-1,3-dioxol-2-one (115 mg) was dropped thereto,the mixture was stirred for 30 minutes. After removal of the bath themixture was further stirred for 30 minutes. Thereto was ethyl acetate,and the mixture was washed with bicarbonate solution, water and brine,successively. The organic layer was dried over sodium sulfate,concentrated and the residue was purified with silica gel columnchromatography (ethyl acetate only) to give(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.11 g, yield 60%).

¹HNMR (400MHz, CDCl₃) δ 1.37 (d, 3H, J=6.0 Hz), 1.73 (d, 1H, J=4.8 Hz),3.18-3.32 (m, 3H),4.24-4.29 (m, 2H), 4.90 (dd, 1H, J=39.6 Hz, 14 Hz),5.90 (d, 1H, J=6.4 Hz), 6.88 (dd, 2H, J=9.2 Hz, 2.8 Hz), 7.30 (dd, 2H,J=9.2 Hz, 2.8 Hz)

Example 5

Allyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.37 g, 3.99 mmol) prepared by Reference Example 3, triphenylphosphine(52 mg), and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol)were dissolved in THF (20 ml), and thereto was added at 0° C. sodium2-ethylhexanoate in ethyl acetate (0.5 M, 8.0 ml, 4.0 mmol), followed bystirring for 1 hour. Thereto was added hexane (30 ml) and the resultingwhite crystals were filtered under a nitrogen atmosphere, washed withhexane, dried at room temperature in vacuo to give a crude product. Theproduct was dissolved in a small amount of ice-water, and purified withC18 reverse column chromatography (filler: Akosil 40C18 (Wako PureChemical Ind.); mobile phase; 0˜5%THF/ice-cooled ion-exchange water).The fractions containing the object compound were combined and THFtherein was removed at room temperature in vacuo under stirring for 1hour. The residue was lyophilized to give sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(297 mg, yield 23%).

LCMS (EI) 304 (M+1).

¹H NMR (400 MHz, DMSO-d6) δ 1.09 (d, 3 H, J=6.3 Hz), 2.82 (dd, 1 H,J=15.6 Hz, 9.9 Hz), 3.01 (dd, 1 H, J=15.6 Hz, 8.5 Hz), 3.08 (dd, 1 H,J=6.5 Hz, 2.8 Hz), 3.63 (s, 3 H), 3.80-3.88 (m, 1 H), 3.92-3.97 (m, 1H), 4.94 (d, 1 H, J=5.0 Hz), 6.62 (ddd, 1 H, J=8.0 Hz, 2.5 Hz, 0.7 Hz),6.94-6.96 (m, 1 H), 7.06 (t, 1 H, J=8.0 Hz), 7.09-7.10 (m, 1 H).

Example 6

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(100 mg) prepared by Example 5, was treated in the same method asExample 1 to give (2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(114 mg, yield 88%).

LCMS (EI) 418 (M+1).

¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9 H), 1.36 (d, 3 H, J=6.3 Hz),3.17-3.55 (m, 3 H), 3.80 (s, 3 H), 4.18-4.32 (m, 2 H), 5.76 (d, 1 H,J=5.5 Hz), 5.85 (d, 1 H, J=5.5 Hz), 6.87-6.92 (m, 3 H), 7.23-7.28 (m, 1H).

Example 7

4-Nitrobenzyl(5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(1.39 g) prepared in accordance to the method described in TetrahedronLetters, 34, 3211-3214 (1993)] was dissolved in THF (28 mL), and theretowere added under ice cooling sodium hydrogencarbonate in ion-exchangewater (28 mL), and 10% palladium-carbon [50% water] (0.14 g). Then theatmosphere was changed with a hydrogen gas, and the mixture was stirredat the same temperature for 3 hours. After filtration of the insolublematerials with Celite, to the filtrate was added chloroform (80 mL). Theorganic layer was separated, and extracted with ion-exchange water (20mL). The organic solvent in the aqueous solution separated and extractedwas removed over one hour period in vacuo, purified with C18 reversecolumn chromatography (Wakosil C18 reverse column, mobile phase;ion-exchange water/THF) and lyophilized to give sodium(5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.44 g, yield 42%).

¹H NMR (400 MHz, D₂O) δ 1.20 (d, 3H, J=6.4 Hz), 1.26 (t, 3H, J=6.8 Hz),2.95 (dd, 1H, J=17.2 Hz, 10.0 Hz), 3.25 (dd, 1H, J=17.2 Hz, 8.4 Hz),3.35-3.38 (m, 1H), 4.02 (q, 2H, J=6.8 Hz), 4.12-4.17 (m, 2H), 6.83 (d,J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H)

Example 8

Sodium(5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.2 g) prepared by Example 8 in dry DMF was ice-cooled, and thereto wasat the same temperature added pivaloyloxymethyl iodide (0.14 g),followed by stirring for 90 minutes. To the reaction mixture were addedethyl acetate and ice water, and the mixture was separated by aseparatory funnel. The organic layer was washed with cooled brine (4times), dried over anhydrous sodium sulfate, and the solvent was removedin vacuo. The residue was purified by silica gel column chromatography(ethyl acetate only) to give [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.15 g, yield 60%).

¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.36 (d, 3H, J=6.4 Hz), 1.41 (t,3H, J=6.8 Hz), 1.81 (d, 1H, J=4.8 Hz), 3.18-3.31 (m, 3H), 4.05 (q, 2H,J=6.4 Hz), 4.23-4.28 (m, 2H), 5.79 (d, 1H, J=5.4 Hz), 5.88 (d, 1H, J=5.4Hz), 6.81 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H)

The following compounds in tables below were prepared in the same 5manners as in Examples 1 to 8.

TABLE 21

Example 9 Example 10 Example 11 R^(a) —H —H —H R^(b) —OEt —OEt —H R^(c)—H —H —OCF₃ R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(400MHz, ¹H NMR(400MHz,¹H NMR(400MHz, data D₂O)δ1.25(d, 3H, J= CDCl₃)δ1.18 D₂O)δ1.19(dd, 3H,6.4Hz), 1.30(t, (s, 9H), 1.37(d, 3H, J=4.0Hz, 6.4Hz), 2.97 3H, J=7.0Hz),3.02 J=6.3Hz), 1.41(t, (dd, 1H, J=16.8Hz, (dd, 1H, J=16.9Hz, 3H,J=7.0Hz), 1.73(d, 10Hz), 3.32(dd, 1H, 9.8Hz), 3.35(dd, 1H, 1H, J=4.9Hz),3.17- J=16.8Hz, 8.4Hz), J=16.9Hz, 8.4Hz), 3.30(m, 3H), 4.02(q,3.39-3.41(m, 1H), 3.42-3.48(m, 1H), 2H, J=7.0Hz), 4.24- 4.13-4.22(m,2H), 4.05(q, 2H, J= 4.31(m, 2H), 5.78(d, 7.18(d, J=8.4Hz, 2H), 7.0Hz),4.16-4.28 1H, J=5.5Hz), 5.86 7.31(d, J=8.4Hz, 2H) (m, 2H), 6.83-6.95 (d,1H, J=5.5Hz), (m, 3H), 7.21-7.29 6.83-6.92(m, 3H), (m, 1H) 6.99-7.26(m,1H)

TABLE 22

Example 12 Example 13 Example 14 R^(a) —H —H —H R^(b) —H —H —H R^(c)—OCF₃ —CH₃ —CH₃ R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹H NMR(400MHz, ¹HNMR(DMSO-d₆, ¹H NMR(CDCl₃, 400 data CDCl₃)δ1.18(s, 9H), 400MHz)δ1.09(d,3 MHz)δ1.19(s, 9H), 1.37(d, 3H, J=6.4Hz), H, J=6.3Hz), 2.18(s, 1.37(d,3H, J=6.3 1.75(d, 1H, J=4.8Hz), 3H), 2.79(dd, 1H, Hz), 1.90(br. d, 1H,3.17-3.34(m, 3H), J=9.8Hz, 15.7Hz), J=4.0Hz), 2.36(s, 3 4.26-4.33(m,2H), 2.99(dd, 1H, J=8.6 H), 3.21(dd, 1H, 5.77(d, 1H, J=5.6Hz), Hz,15.7Hz), 3.05 J=9.8Hz, 18.3Hz), 5.87(d, 1H, J=5.6Hz), (dd, 1H, J=2.8Hz,3.24(dd, 1H, J=2.8 7.19(d, J=8.0Hz, 2H), 6.6Hz), 3.80-3.88 Hz, 6.8Hz),3.31(dd, 7.39(d, J=8.0Hz, 2H) (m, 1H), 3.90-3.97 1H, J=8.9Hz, 18.3 (m,1H), 4.93(d, 1H, Hz), 4.21-4.31(m, 2 J=5.0Hz), 6.95(br. H), 5.77(d, 1H,d, 2H, J=8.0Hz), J=5.5Hz), 5.87(d, 1 7.29-7.3 1(m, 2H). H, J=5.5Hz),7.16 LCMS(EI)288 (br. d, 2H, J=8.0Hz), (M+1+). 7.26(br. d, 2H, J=8.2Hz). LCMS(EI)402 (M+1+).

TABLE 23

Example 15 Example 16 Example 17 R^(a) —H —H —H R^(b) —CH₃ —CH₃ —H R^(c)—H —H —CH₂OCH₃ R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(D₂O, 300 ¹HNMR(CDCl₃, 300 ¹H NMR(DMSO-d₆, data MHz)δ1.15(d, 3H, J= MHz)δ1.18(s,9H), 400MHz)δ1.09(d, 3 6.4Hz), 2.16(s, 3 1.37(d, 3H, J=6.2 H, J=6.3Hz),2.81 H), 2.91(dd, 1H, J= Hz), 2.35(s, 3H), (dd, 1H, J=9.8Hz, 9.7Hz,16.8Hz), 3.27 3.15-3.36(m, 3H), 15.7Hz), 3.03(dd, 1 (dd, 1H, J=8.4Hz,4.23-4.33(m, 2H), H, J=8.5Hz, 15.7 16.8Hz), 3.35(dd, 1 5.77(d, J=5.5Hz),Hz), 3.08(dd, 1H, J= H, J=2.8Hz, 6.0Hz), 5.85(d, J=5.5Hz), 2.8Hz,6.6Hz), 3.18 4.06-4.18(m, 2H), 7.12-7.24(m, 4H). (s, 3H), 3.81-3.88(m,6.98-7.15(m, 4 H). IR(ATR)2974, 1751, 1H), 3.91-3.97(m, 1 IR(ATR)1743,1585, 1481, 1458, 1340, H), 4.28(s, 2H), 4.94 1389, 1308, 1250, 1267,1182, 1120, (d, 1H, J=4.9Hz), 1223, 1134, 1001, 1095, 1022, 980, 785,7.09(br. d, 2H, J= 947, 783, 694 cm⁻¹. 731, 696 cm⁻¹. 8.3Hz), 7.38(br.d, 2 LCMS(EI)288(M+1+). LCMS(EI)402(M+1+). H, J=8.3Hz). IR(ATR)3491,3342, 2980, 2922, 2891, 1780, 1742, 1585, 1516, 1379, 1306, 1248, 1213,1159, 1138, 1099, 1068, 962, 933, 847, 816, 783, 708, 677, 638 cm⁻¹.LCMS(EI)318(M+1+).

TABLE 24

Example 18 Example 19 Example 20 R^(a) —H —H —H R^(b) —H —H —H R^(c)—CH₂OCH₃ —Cl —Cl R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹H NMR(CDCl₃,400 ¹H NMR(400MHz, ¹H NMR(400MHz, data MHz)δ1.19(s, 9H), D₂O)δ1.17(d,3H, CDCl₃)δ1.18(s, 9H), 1.37(d, 3H, J=6.3 J=6.4Hz), 2.94(dd, 1.37(d, 3H,Hz), 1.83(d, 1H, J= 1H, J=16.9Hz, 9.8Hz), J=6.3Hz), 1.74(d, 4.8Hz),3.22(dd, 1H, 3.30(dd, 1H, J= 1H, J=4.8Hz), 3.14- J=9.9Hz, 18.3Hz),16.9Hz, 8.4Hz), 3.35- 3.35(m, 3H), 4.19- 3.26(dd, 1H, J=2.7 3.41(m,1H),4.08- 4.34(m, 2H), 5.76(d, Hz, 6.9Hz), 3.33(dd, 4.20(m, 2H), 7.16- 1H,J=5.5Hz), 5.87 1H, J=8.9Hz, 18.3 7.21(m,2H), 7.21- (d, 1H, J=5.5Hz),Hz), 4.23-4.33(m, 2 7.27(m,2H) 7.22-7.35(m, 4H) H), 5.77(d, 1H, J=5.5Hz), 5.87(d, 1H, J=5.5Hz), 7.31- 7.38(m, 4 H). LCMS(EI)432(M+1+).

TABLE 25

Example 21 Example 22 Example 23 R^(a) —H —H —H R^(b) —H —H —F R^(c) —F—F —H R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(400MHz, ¹H NMR(400MHz, ¹HNMR(400MHz, data D₂O)δ1.03(d, 3H, CDCl₃)δ1.18(s, 9H), D₂O)δ1.18(d, 3H,J=6.4Hz), 2.80(dd, 1.37(d, 3H, J=6.4Hz), 2.96(dd, 1H, J=16.8Hz,J=6.4Hz), 3.17-3.33 1H, J=16.8Hz, 10Hz), 8.4Hz), 3.14(dd, 1H, (m, 3H),4.25-4.32 3.24(dd, 1H, J=16.8Hz, 8.4Hz), (m, 2H), 5.76(d, 1H, J=16.8Hz,8.4Hz), 3.21-3.23(m, 1H), J=5.4Hz), 5.87(d, 3.39-3.40(m, 1H),3.96-4.05(m, 2H), 1H, J=5.4Hz), 6.99- 4.11-4.20(m, 2H), 6.79-6.85(m,2H), 7.06(m, 2H), 7.33- 6.92-7.04(m, 3H), 7.06-7.10(m, 2H) 7.37(m, 2H)7.20-7.24(m, 1H)

TABLE 26

Example 24 Example 25 Example 26 R^(a) —H —F —F R^(b) —F —H —H R^(c) —H—H —H R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹H NMR(400MHz, ¹HNMR(400MHz, ¹H NMR(400MHz, data CDCl₃)δ1.18(s, 9H), D₂O)δ1.17(d, 3H,CDCl₃)δ1.17(s, 9H), 1.37(d, 3H, J=6.4Hz), 2.85(dd, 1.37(d, 3H, J=6.4Hz),J=6.4Hz), 1.80(d, 1H, J=16.4Hz, 9.6Hz), 1.74(d, 1H, J=4.4Hz), 1H,J=4.4Hz), 3.16- 3.29(dd, 1H, 3.14-3.36(m, 3H), 3.34(m, 3H), 4.24-J=16.4Hz, 8.8Hz), 4.27-4.37(m, 2H), 4.33(m, 2H), 5.76(d, 3.35-3.37(m,1H), 5.72(d, 1H, J=5.4Hz), 1H, J=5.4Hz), 5.86 4.08-4. 19(m, 2H), 5.81(d,1H, J=5.4Hz), (d, 1H, J=5.4Hz), 6.97-7.06(m, 2H), 7.04-7.34(m, 4H)7.02-7.12(m, 3H), 7.14-7.19(m, 2H) 7.30-7.32(m,1H)

TABLE 27

Example 27 Example 28 Example 29 R^(a) —H —H —H R^(b) —H —H —H R^(c) —CN—CN —SO₂NHMe R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(400MHz, ¹HNMR(400MHz, ¹H NMR(400MHz, D₂O) data D₂O)δ1.16(d, 3H, CDCl₃)δ1.18(s,9H), δ1.26(d, 3H, J=6.4Hz), J=6.4Hz), 2.97(dd, 1.37(d, 3H, 2.50(s, 3H),3.08(dd, 1H, J=16.9Hz, J=6.3Hz), 1.78(br s, 1H, J=16.9Hz, 9.9Hz),9.9Hz), 3.31(dd, 1H), 3.15-3.40(m, 3.43(dd, 1H J=16.9Hz, 1H, J=16.9Hz,3H), 4.25-4.40(m, 8.5Hz), 3.47-3.53(m, 8.5Hz), 3.36-3.43 2H), 5.76(d,1H, 1H), 4.17-4.24(m, 1H), (m, 1H), 4.06-4.14 J=5.5Hz), 5.86(d,4.24-4.36(m, 1H), 7.50 (m, 1H), 4. 14-4.22 1H, J=5.5Hz), 7.40- (d, 2H,J=8.6Hz), 7.75 (m, 1H), 7.25-7.36 7.46(m, 2H), 7.60- (d, 2H, zJ=8.6Hz)(m, 2H), 7.52-7.80 7.68(m, 2H) (m, 2H)

TABLE 28

Example 30 Example 31 R^(a) —H —H R^(b) —H —H R^(c) —OCH₂CH₂OCH₃—OCH₂CH₂OCH₃ R —Na —CH₂OCOt-Bu Physical ¹H NMR(D₂O, 300MHz)δ1.16(d, ¹HNMR(CDCl₃, 300MHz)δ1.20 data 3H, J=6.4Hz), 2.91(dd, 1H, (s, 9H), 1.37(d,3H, J=6.4Hz), J=9.5Hz, 17.0Hz), 3.26(dd, 1H, 3.20-3.28(m, 3H), 3.45(s,3H), J=8.8Hz, 16.9Hz), 3.29(s, 3H), 3.74-3.77(m, 2H), 4.12-4.16(m,3.33(dd, 1H, J=2.6Hz, 6.0Hz), 2H), 4.22-4.30(m, 2H), 5.79(d,3.66-3.69(m, 2H), 4.06-4.17(m, 1H, J=5.5Hz), 5.88(d, 1H, J=5.5 4H),6.81-6.91(m, 2H), 7.17- Hz), 6.87-6.92(m, 2H), 7.33-7.39 7.22(m, 2H).(m, 2H). IR(ATR)1781, 1585, 1511, 1456, IR(ATR)2974, 1774, 1751, 1604,1383, 1288, 1250, 1219, 1192, 1510, 1456, 1340, 1248, 1182, 1138, 1124,1068, 1035, 924, 1124, 1093, 1022, 978, 829, 767 860, 827, 802, 777, 710cm⁻¹. cm⁻¹. LCMS(EI)348(M+1+). LCMS(EI)462(M+1+).

Example 32

Sodium(5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.2 g) in dry DMF (4.0 ml) was ice-cooled. Thereto ware addedtetrabutylammonium iodide (0.53 g), and 4-(2-chloroethyl)-morpholine (1Mtoluene, 8 mL), and the mixture was stirred. Thirty minutes later, afterremoval of the bath the mixture was stirred for 48 hours and thereto wasadded ethyl acetate. The mixture was washed succesively with aqueousphosphate buffer (pH 6.86), water and brine. The organic layer was driedover sodium sulfate, concentrated, and the residue was purified withsilica gel column chromatography (chloroform:methanol=1:0→10:1) to give2-morpholin-4-ylethyl(5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.10 g, yield 33%).

¹HNMR (400 MHz, CDCl₃) δ 1.37 (d, 3H, J=6.4 Hz),1.72 (s, 1H), 2.40-2.51(m, 4H), 2.58-2.65 (m, 2H), 3.16-3.37 (m, 3H), 3.60-3.62 (m, 4H),4.22-4.40 (m, 4H), 7.47 (d, 2H, J=8.4 Hz), 7.64 (d, 2H, J=8.4 Hz)

Example 33

Allyl(5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.807 g), tetrakis(triphenylphosphine)palladium(0) (50 mg) andtriphenylphosphine (10 mg) were dissolved in THF (12 mL), and theretowas added at room temperature sodium 2-ethylhexanoate (0.5M ethylacetate solution, 4.46 mL). The solvent was removed in vacuo, and to theresidue was added dichloromethane (10 mL). The mixture was extractedwith ion-exchange water (10 mL×3 times) and the aqueous layers werecombined and stirred for 1 hour in vacuo. The dichloromethane wasremoved by distillation and the aqueous layer was purified with C18reverse column chromatography (Wakosil 40C18, 38φ×60 mm, mobile phase;0˜5% THF ice-cooled ion-exchange water). The fractions containing theobject compound were combined and THF therein was removed in vacuo understirring for 1 hour. The residue was lyophilized to give sodium(5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(450 mg, yield 59%).

¹H NMR (400 MHz, DMSO-d₆) δ 1.08 (d, 3 H, J=6.3 Hz), 2.83 (dd, 1 H,J=9.9 Hz, 15.7 Hz), 2.97 (dd, 1 H, J=8.5 Hz, 15.7 Hz), 3.06 (dd, 1 H,J=2.8 Hz, 6.6 Hz), 3.76 (s, 3 H), 3.80-3.88 (m, 1 H), 3.89-3.95 (m, 1H), 4.94 (d, 1 H, J=5.0 Hz), 6.94 (t, 1 H, J=9.0 Hz), 7.06-7.10 (m, 1H), 7.56 (dd, 1 H, J=2.1 Hz, 14.1 Hz).

LCMS (EI) 322 (M+1⁺).

Example 34

To sodium(5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(100 mg) in DMF (3 mL) was added at 0° C. pivaloyloxymethyl iodide (77mg), and the mixture was stirred for 15 minutes. To the reaction mixturewas added diethyl ether (50 mL), and the mixture was washed withsaturated brine (50 mL×3times), dried over magnesium sulfate, filtered,and the solvent was removed in vacuo. The residue was purified undersilica gel column chromatography (chloroform:methanol=100:0˜100:3) togive [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(70 mg, 55%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9 H), 1.36 (d, 3 H. J=6.3 Hz), 3.20(dd, 1 H, J=9.9 Hz, 18.2 Hz), 3.23-3.26 (m, 1 H), 3.29 (dd, 1 H, J=9.0Hz, 18.2 Hz), 3.91 (s, 3 H), 4.22-4.31 (m, 2 H), 5.80 (d, 1 H, J=5.5Hz), 5.89 (d, 1 H, J=5.5 Hz), 6.90-6.95 (m, 1 H), 7.15-7.20 (m, 2 H).

LCMS (EI) 436 (M+1⁺).

The compounds listed in tables below were prepared in the same manner asin Example 33 and Example 34.

TABLE 29

Example 35 Example 36 Example 37 R^(a) —H —H —H R^(b) —OCH₃ —OCH₃ —OCH₃R^(c) —F —F —OCH₃ R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(DMSO-d₆, ¹HNMR(CDCl₃, 400 ¹H NMR(400MHz, data 400MHz)δ1.15(d, 3 MHz)δ1.17(s, 9H),D₂O)δ1.18(d, 3H, H, J=6.3Hz), 2.92 1.36(d, 3H, J=6.3 J=5.4Hz), 2.90(dd,(dd, 1H, J=9.9Hz,Hz), 3.22(dd, 1H, J= 1H, J=16.8Hz, 15.8Hz), 3.08(dd, 19.9Hz, 18.3Hz), 9.6Hz), 3.22(dd, 1H, H, J=8.5Hz, 15.8 3.25-3.27(m, 1H),J=16.8Hz, 8.4Hz), Hz), 3.14(dd, 1H, 3.29(dd, 1H, J=9.0 3.31-3.33(m, 1H),J=2.8Hz, 6.5Hz), Hz, 18.4Hz), 3.89(s, 3.69(s, 3H), 3.72(s, 3.77(s, 3H),3.89- 3H), 4.21-4.32(m, 2 3H), 4.08-4.15(m, 3.94(m, 1H), 3.98- H),5.78(d, 1H, J= 2H), 6.77-6.88(m, 4.03(m, 1H), 5.01 5.5Hz), 5.86(d, 1H,2H), 6.93(s, 1H) (d, 1H, J=4.9Hz), J=5.5Hz), 6.88 6.96 (ddd, 1H, J=2.1(ddd, 1H, J=2.1Hz, 4.3Hz, 8.4Hz), 7.04 Hz, 4.5Hz, 8.5Hz), (dd, 1H,J=8.4Hz, 7.04(dd, 1H, J=8.5 10.9Hz), 7.07-7.09 Hz, 11.4Hz), 7.57 (m,1H). (dd, 1H, J=2.0Hz, LCMS(EI)436 8.8Hz). (M+1+). IR(ATR)3336, 2970,1743, 1597, 1516, 1454, 1392, 1323, 1304, 1261, 1238, 1223, 1207, 1176,1122, 1026, 949, 906, 852, 810, 771, 702 cm⁻¹. LCMS(EI)322 (M+1+).

TABLE 30

Example 38 Example 39 Example 40 R^(a) —H —H —H R^(b) —OCH₃ —CH₃ —CH₃R^(c) —OCH₃ —OCH₃ —OCH₃ R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹HNMR(400MHz, ¹H NMH(400MHz, ¹H NMH(400MHz, data CDCl₃)δ1.18(s, 9H),D₂O)δ1.20(d, 3H, CDCl₃)δ1.19(s, 9H), 1.37(d, 3H, J=6.4Hz), 2.06(s,1.37(d, 3H, J=6.3Hz), J=6.0Hz), 1.69(d, 3H), 2.93(dd, 1H, 1.78(d, 1H,J=4.9Hz), 1H, J=4.8Hz), 3.21- J=16.9Hz, 9.7Hz), 2.20(s, 3H), 3.15-3.31(m, 3H), 3.88(s, 3.28(dd, 1H, 3.33(m, 3H), 3.85(s, 3H), 3.90(s, 3H),J=16.9Hz, 8.6Hz), 3H), 4.20-4.3 1(m, 4.24-4.29(m, 2H), 3.33-3.39(m, 1H),2H), 5.80(d, 1H, 5.81(d, 1H, 3.74(s, 3H), 4.08- J=5.5Hz), 5.88(d, 1H,J=5.6Hz), 5.88(d, 4.22(m, 2H), 6.82- J=5.5Hz), 6.79(d, 1H, 1H, J=5.6Hz),6.82 6.89(m, 1H), 7.00- J=8.5Hz), 7.17(s, (d, 1H, J=8.4Hz), 7.14(m, 2H)1H), 7.23-7.27(m, 6.98(dd, 1H, 1H) J=8.4Hz, 2.0Hz), 7.07(d, 1H, J=2.0Hz)

TABLE 31

Example 41 Example 42 Example 43 R^(a) —H —H —H R^(b) —Cl —Cl —NH₂ R^(c)—NH₂ —NH₂ —Cl R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(400MHz, ¹HNMR(400MHz, ¹H NMR(400MHz, data D₂O)δ1.25(d, 3H, CDCl₃)δ1.21(s, 9H),D₂O)δ1.22(d, 3H, J=6.4Hz), 2.98(dd, 1.36(d, 3H, J=6.3Hz), J=6.4Hz),2.97(dd, 1H, J=16.8Hz, 9.7Hz), 1.81(br s, 1H), 3.13- 1H, J=17.0Hz,9.8Hz), 3.30(dd, 1H, 3.30(m, 3H), 4.19- 3.30(dd, 1H, J= J=16.8Hz,8.6Hz), 4.28(m, 4H), 5.81(d, 7.0Hz, 8.4Hz), 3.39- 3.37-3.44(m, 1H), 1H,J=5.5Hz), 5.89(d, 3.45(m,1H), 4.12- 4.12-4.25(m, 2H), 1H, J=5.5Hz),6.70(d, 4.25(m, 2H), 6.70 6.85(d, 1H, J=8.4Hz), 1H, J=8.4Hz), 7.21 (dd,1H, J=8.3Hz, 7.11(dd. 1H, (dd, 1H,J=8.4Hz, 2.1Hz), 6.83(d. 1H, J=8.4Hz,2.1Hz), 7.29 2.0Hz), 7.37(d, 1H, J=2.1Hz), 7.21(d. 1H, (d. 1H, J=2.0Hz)J=8.4Hz) J=8.3Hz)

TABLE 32

Example 44 Example 45 Example 46 R^(a) —H —H —H R^(b) —NH₂ —NH₂ —NH₂R^(c) —Cl —OCH₃ —OCH₃ R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹HNMR(400MHz, ¹H NMR(400MHz, ¹H NMR(400MHz, data CDCl₃)δ1.18(s, 9H),D₂O)δ1.19(d, 3H, CDCl₃)δ1.19(s, 9H), 1.36(d, 3H, J=6.3Hz), J=6.4Hz),2.92(dd, 1.37(d, 3H, J=6.3Hz), 1.78(d, 1H, 1H, J=16.9Hz, 9.7Hz), 1.76(brs, 1H), 3.13- J=4.78Hz), 3.11-3.32 3.25(dd, 1H, 3.30(m, 3H), 3.87(s, (m,3H), 4.07-4.20(m, J=16.9Hz, 8.6Hz), 3H), 4.18-4.31(m, 2H), 4.21-4.31(m,3.31-3.39(m, 1H), 2H), 5.80(d, 1H, 2H), 5.77(d, 1H, 3.74(s, 3H), 4.08-J=5.5Hz), 5.87(d, 1H, J=5.5Hz), 5.86(d, 1H, 4.20(m, 2H), 6.66- J=5.5Hz),6.65-7.01 J=5.5Hz), 6.63(dd, 6.79(m, 2H), 6.81(d, (m, 3H) 1H, J=8.3Hz,2.0Hz), 1H, J=8.4Hz) 6.79(d, 1H, J=2.0Hz), 7.20(d, 1H, J=8.3Hz)

TABLE 33

Example 47 Example 48 Example 49 R^(a) —H —H —H R^(b) —NH₂ —NH₂ —F R^(c)—CH₃ —CH₃ —NH₂ R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(400MHz, ¹HNMR(400MHz, ¹H NMR(400MHz, data D₂O)δ1.19(d, 3H, CDCl₃)δ1.19(s, 9H),D₂O)δ1.17(d, 3H, J=6.4Hz), 2.04(s, 1.37(d, 3H, J=6.4Hz), 2.86(dd, 3H),2.93(dd, 1H, J=6.3Hz), 1.73(d, 1H, J=16.8Hz, J=16.9Hz, 9.8Hz), 1H,J=4.9Hz), 2.16(s, 9.6Hz), 3.18(dd, 1H, 3.27(dd, 1H, 3H), 3.12-3.29(m,J=16.8Hz, 8.4Hz), J=16.9Hz, 8.5Hz), 3H), 3.68(br s, 2H), 3.28-3.30(m,1H), 3.38(dd, 1H, 4.20-4.30(m, 2H), 4.06-4.12(m, 2H), J=6.4Hz, 2.8Hz),5.78(d, 1H, 6.73(t, 1H, 4.08-4.21(m, 2H), J=5.5Hz), 5.86(d, J=8.4Hz),6.87(dd, 6.67(dd, 1H, 1H, J=5.5Hz), 6.67 1H, J=8.4Hz, 2.0Hz), J=7.7Hz,1.6Hz), (dd, 1H, J=7.7Hz, 6.96(dd, 1H, 6.70(d, 1H, 1.7Hz), 6.71(d, 1H,J=8.8Hz, 2.0Hz) J=1.6Hz), 6.99(d, J=1.7Hz), 7.00(d, 1H, J=7.7Hz) 1H,J=7.7Hz)

TABLE 34

Example 50 Example 51 Example 52 R^(a) —H —H —H R^(b) —F —F —F R^(c)—NH₂ —NHCOCH₃ —NHCOCH₃ R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹HNMR(400MHz, ¹H NMR(400MHz, ¹H NMR(400MHz, data CDCl₃)δ1.20(s, 9H),D₂O)δ1.17(d, 3H, CDCl₃)δ1.20(s, 1.36(d, 3H, J=5.6Hz), 2.06(s, 9H),1.37(d, H, J=6.0Hz), 1.77(d, 3H), 2.95(dd, 1H, J=6.4Hz), 1.77(d, 1H,J=4.8Hz), 3.16- J=16.8Hz, 10Hz), 1H, J=4.8Hz), 2.23 3.27(m, 3H), 3.933.28(dd, 1H, (s, 3H), 3.17-3.33 (br s, 2H), 4.21-4.27 J=16.8Hz, 8.8Hz),(m, 3H), 4.24-4.31 (m, 2H), 5.81(d, 1H, 3.37-3.39(m, 1H), (m, 2H),5.79(d, 1H, J=6.4Hz), 5.90(d, 4.06-4.22(m, 2H), J=5.6Hz), 5.88(d, 1H,J=6.4Hz), 6.70 7.02-7.09(m, 2H), 1H, J=5.6Hz), 7.12 (t, 1H, J=8.4Hz),7.42(t, 1H, J=8.0Hz) (d, 1H, J=8.4Hz), 7.06(dd, 1H, 7.20(m, 1H), 7.40J=8.4Hz, 1.0Hz), (s, 1H), 8.34(t, 1H, 7.16(dd, 1H, J=8 .0Hz) J=12.4Hz,1.0Hz)

TABLE 35

Example 53 Example 54 R^(a) —H —H R^(b) —F —F R^(c) —NHCOOCH₃ —NHCOOCH₃R Na —CH₂OCOt-Bu Physical ¹H NMR(400MHz, D₂O)δ1.22 ¹H NMR(400MHz,CDCl₃)δ data (d, 3H, J=6.4Hz), 3.01(dd, 1H, 1.19(s, 9H), 1.36(d, 3H,J=17.2Hz, 9.6Hz), 3.30(dd, 1H, J=6.4Hz), 1.78(d, 1H, J=4.8Hz), J=17.2Hz,8.4Hz), 3.42-3.44(m, 3.17-3.33(m, 3H), 3.81(s, 3H), 1H), 4.16-4.22(m,2H), 7.07- 4.24-4.31(m, 2H), 5.79(d, 1H, 7.13(m, 2H), 7.55(t, 1H,J=5.6Hz), 5.88(d, 1H, J=5.6Hz), J=8.0Hz) 6.99(s, 1H), 7.14(d, 1H,J=8.8Hz), 7.20-7.23(m, 1H), 8.10(brs, 1H)

TABLE 36

Example 55 Example 56 Example 57 R^(a) —H —H —H R^(b) —CONH₂ —Cl —ClR^(c) —OCH₃

R —Na —Na —CH₂OCOt-Bu Physical ¹H NMR(D₂O, ¹H NMR(D₂O, ¹H NMR(CDCl₃,data 400MHz) · 1.25(d, 300MHz) · 1.20(d, 300MHz) · 1.21(s, 3H, J=6.4Hz),3.02 3H, J=6.4Hz), 2.97 9H), 1.37(d, 3H, (dd, 1H, J=17.0Hz, (dd, 1H,J=16.8Hz, J=6.2Hz), 3.18-3.38 9.8Hz), 3.37(dd, 9.7Hz), 3.29(dd, (m, 3H),4.24-4.36 1H, J=17.0Hz, 1H, J=16.8Hz, (m, 2H), 5.81(d, 1H, 8.6Hz),3.44(dd, 8.4Hz), 3.40(dd, J=5.5Hz), 5.89(d, 1H, J=6.0Hz, 1H, J=5.9Hz,1H, J=5.5Hz), 7.36 2.7Hz), 3.90(s, 3H), 2.7Hz), 4.10-4.23 (dd, 1H,J=8.6Hz, 3.95-3.98(m, 1H), (m, 2H), 7.25(dd, 2.0Hz), 7.54(d, 1H,4.21-4.24(m, 1H), 1H, J=8.4Hz, J=2.0Hz), 7.73-7.76 7.08(d, 1H, 1.9Hz),7.42(d, 1H, (m, 2H), 8.52(br s, J=8.8Hz), 7.50(dd, J=1.9Hz), 7.45(d,1H), 8.57(d, 1H, 1H, J=8.7Hz, 1H, J=8.4Hz), 7.73- J=8.6Hz), 8.85-8.872.4Hz), 7.69(d, 1H, 7.75(m, 2H), 8.61- (m, 2H). J=2.4Hz). 8.63(m, 2H).IR(ATR)1751, LCMS(EI)347 IR(ATR)751, 1686, 1599, 1572, (M+1+). 1664,1578, 1516, 1514, 1479, 1394, 1389, 1308, 1254, 1369, 1261, 1192, 1221,1130, 1055, 1116, 1095, 1053, 1001, 897cm⁻¹. 1024, 980, 887, 827 cm⁻¹.

TABLE 37

Example 58 Example 59 Example 60 R^(a) —H —H —H R^(b) —Cl —Cl —Cl R^(c)

R —Na —CH₂OCOt-Bu —Na Physical ¹H NMR(D₂O, 300 ¹H NMR(CDCl₃, ¹H NMR(D₂O,300 data MHz) · 1.19(d, 3H, 300MHz) · 1.20 MHz) · 1.20(d, 3 J=6.4Hz),2.99(dd, (s, 9H), 1.37(d, 3 H, J=6.6Hz), 3.00 1H, J=16.8Hz,9.7 H,J=6.2Hz), (dd, 1H, J=16.7 Hz), 3.30(dd, 1H, J= 3.17-3.36(m, 3H), Hz,10.3Hz), 3.31 16.8Hz, 8.2Hz), 4.23-4.34(m, 2H), (dd, 1H, J=16.7 3.41(dd,1H, J= 5.81(a, 1H, J= Hz, 8.4Hz), 3.42 6.0Hz, 2.7Hz), 5.5Hz), 5.89(d, 1(dd, 1H, J=6.0Hz, 4.10-4.22(m, 2H), H, J=5.5Hz), 6.60 2.7Hz), 4.10-4.236.58(dd, 1H, J= (dd, 1H, J=3.5 (m, 2H), 6.26-6.28 3.7Hz, 1.7Hz), 7.21Hz, 1.8Hz), 7.29 (m, 1H), 6.94(d, 1 (dd, 1H, J=3.7Hz, (dd, 1H, J=3.5 H,J=3.9Hz), 7.04- 0.9Hz), 7.24(dd, 1 Hz, 0.9Hz), 7.32 7.05(m, 1H), 7.22-H, J=8.4Hz, 2.0 (dd, 1H, J=8.6 7.26(m, 1H), 7.39- Hz), 7.43(d, 1H, J=Hz, 2.0Hz), 7.52 7.43(m, 2H). 2.0Hz), 7.47(d, 1H, (d, 1H, J=2.0Hz),LCMS(EI)416 J=8.4Hz), 7.64(dd, 7.57(dd, 1H, J= (M+1+). 1H, J=1.7Hz, 0.91.8Hz, 0.9Hz), Hz). 8.56(d, 1H, J= IR(ATR) 1749, 1676, 8.6Hz), 8.77(brs, 1589, 1518, 1462, 1H). 1389, 1308, 1261, IR(ATR) 1751, 1228, 1165,1138, 1686, 1589, 1514, 1113, 1049, 1011, 1460, 1396, 1313, 885,750cm⁻¹. 1261, 1192, 1160, 1097, 1022, 980, 883, 823, 758cm⁻¹. LCMS(EI)531 (M+1+).

TABLE 38

Example 61 Example 62 Example 63 R^(a) —H —H —H R^(b) —Cl —CN —CN R^(c)

—OMe —OMe R —CH₂OCOt-Bu —Na —CH₂OCOt-Bu Physical ¹H NMR(CDCl₃, ¹HNMR(D₂O, 300 ¹H NMR(CDCl₃, data 300MHz) · 1.20 MHz) · 1.15(d, 300MHz) ·1.20 (s, 9H), 1.37(d, 3 3H, J=6.4Hz), 2.89(dd, (s, 9H), 1.37(d, 3 H,J=6.4Hz), 1H, J=16.8 H, J=6.4Hz), 3.17-3.36(m, 3H), Hz, 9.7Hz), 3.233.15-3.34(m, 3H), 4.25-4.34(m, 2H), (dd, 1H, J=16.8 3.97(s, 3H), 4.23-5.80(d, 1H, J= Hz, 8.4Hz), 3.33 4.34(m, 2H), 5.79 5.5Hz), 5.89(d, 1 (dd,1H, J=6.0 (d, 1H, J=5.5Hz), H, J=5.5Hz), Hz, 2.7Hz), 4.03- 5.88(d, 1H,J= 6.31-6.35(m, 1H), 4.17(m, 2H), 6.96 5.5Hz), 6.97(d, 1 6.78-6.81(m,1H), (d, 1H, J=9.2Hz), H, J=9.0Hz), 7.58 7.03-7.06(m, 1H), 7.44-7.48(m,2H). (d, 1H, J=2.2Hz), 7.29-7.33(m, 1H), 7.65(dd, 1H, J= 7.51-7.52(m,1H), 9.0, 2.2Hz). 8.25(br s, 1H), 8.49-8.52(m, 1H), 9.59(br s, 1H).

TABLE 39

Example 64 Example 65 Example 66 R^(a) —H —H —H R^(b) —Cl —Cl —Cl R^(c)—OCH₃ —OCH₃ —OCH₃ R —Na —CH₂OCOt-Bu

Physical ¹H NMR(400MHz, ¹H NMR(400MHz, ¹H NMR(400MHz, data D₂O)δ1.11(d,3H, CDCl₃)δ1.20(s, 9H), CDCl₃)δ1.37(d, 3H, J=6.4Hz), 2.86(dd, 1H,1.36(d, 3H, J=6.3Hz), 1.79(d, J=17.0Hz, J=6.3Hz), 1.79(d, 1H, J=4.7Hz),2.16 9.8Hz), 3.17(dd, 1H, 1H, J=4.8Hz), 3.17- (s, 3H), 3.17-3.32(m,J=17.0Hz, 8.5Hz), 3.31(m, 3H), 3.93(s, 3H), 3.93(s, 3H), 3.29-3.31(m,1H), 3H), 4.24-4.31(m, 4.25-4.31(m, 2H), 3.72(s, 3H), 4.03- 2H), 5.80(d,1H, 4.88(d, 1H, 4.12(m, 2H), 6.90(d, J=5.5Hz), 5.88(d, J=13.9Hz),4.97(d, 1H, J=9.7Hz), 7.11 1H, J=5.5Hz), 6.90 1H, J=13.9Hz), 6.91 (dd,1H, J=8.6Hz, (d, 1H, J=8.6Hz), (d, 1H, J=8.6Hz), 2.2Hz), 7.25(d, 1H,7.33(dd, 1H, 7.25-7.28(m, 1H), J=2.2Hz) J=8.6Hz, 2.2Hz), 7.38(d, 1H,J=2.2Hz) 7.41(d, 1H, J=2.2Hz)

TABLE 40

Example 67 Example 68 R^(a) —H —H R^(b) —Cl —Cl R^(c)

R —Na —CH₂OCOt-Bu Physical ¹H NMR(400MHz, CDCl₃) δ ¹H NMR(400MHz, CDCl₃)δ data 1.12(d, 3H, J=6.4Hz), 2.90(dd, 1.18(s, 9H), 1.35(d, 3H, 1H,J=17.0Hz, 9.9Hz), 3.22(dd, J=6.3Hz), 1.81(br s, 1H), 3.14- 1H, J=17.0Hz,8.5Hz), 3.33(m, 3.31(m, 3H), 3.79(s, 2H), 4.26- 1H), 3.73(s, 2H),4.06-4.15(m, 4.31(m, 2H), 5.77(d, 1H, 2H), 7.13(dd, 1H, J=8.4Hz,J=5.5Hz), 5.86(d, 1H, 2.0Hz), 7.23-7.37(m, 4H), 8.33 J=5.5Hz),7.24-7.27(m, 1H), (dd, 2H, J=4.6Hz, 1.6Hz) 7.31(d, 2H, J=4.5Hz), 7.42(d,1H, J=2.0Hz), 7.69(br s, 1H), 8.38(d, 1H, J=8.6Hz), 8.65(d, 2H, J=4.4Hz)

TABLE 41

Example 69 Example 70 R^(a) —H —H R^(b) —NH₂ —NH₂ R^(c)

R —Na —CH₂OCOt-Bu Physical ¹H NMR(400MHz, DMSO-d₆)δ ¹H NMR(400MHz,CDCl₃)δ data 1.16(d, 3H, J=6.3Hz), 2.84 1.17(s, 9 H), 1.34(d, 3H, J=(dd, 1H, J=9.8Hz, 16.0Hz), 6.3Hz), 3.13(dd, 1H, J=18.4 3.08(dd, 1H,J=8.6Hz, 16.0 Hz, 9.9Hz), 3.20-3.27(m, 2H), Hz), 3.16(dd, 1H, J=2.7Hz,3.55(s, 2H), 4.18-4.28(m, 2H), 6.6Hz), 3.37(s, 2H), 3.84-3.88 4.40(d,2H, J=6.2Hz), 5.67(d, (m, 1H), 4.02(td, 1H, J=9.2 1H, J=5.5Hz), 5.76(d,1H, J= Hz 2.6Hz), 4.28(d, 2H, J=6.1 5.5Hz), 6.65(dd, 1H, J=7.7 Hz),5.01(br s, 2H), 6.69(d, 1H, Hz, 1.7Hz), 6.70(d, 1H, J=1.7 J=1.6Hz),6.75(dd, 1H,J=Hz), 6.74(t, 1H, J=6.7Hz), 7.8Hz, 1.6Hz), 6.90(d, 1H, J=7.02(d, 1H, J=7.7Hz), 7.11- 7.8Hz), 7.20-7.23(m, 2H), 7.13(m, 2H),8.46-8.47(m, 2H). 8.46-8.48(m, 2H), 8.71(t, 1H, J=6.0Hz).LCMS(EI)551(M+1)⁺. LCMS(EI)437(M−Na+1)⁺.

TABLE 42

Example 71 Example 72 R^(a) —H —H R^(b) —Cl —NH₂ R^(c) —NHCOCH₂NH₂ —OH R—H —Na Physical ¹H NMR(400MHz, D₂O)δ1.17 ¹H NMR(400MHz, D₂O)δ1.15 data(d, 3H, J=5.6Hz),, 2.98(dd, 1H, (d, 3H, J=5.6Hz),, 2.86(dd, 1H,J=16.8Hz, 10Hz), 3.30(dd, 1H, J=17.2Hz, 10Hz), 3.30(dd, 1H, J=16.8Hz,8.4Hz), 3.40-3.42(m, J=17.2Hz, 8.4Hz), 3.30-3.32(m, 1H), 4.13-4.23(m,2H), 7.21- 1H), 4.07-4.13(m, 2H), 6.58- 7.23(m, 2H), 7.40(s, 1H),7.44-7.48(m, 2H) 6.67(m, 2H), 6.78(s, 1H)

Example 73

Allyl(5R,6S)-3-(4-{2-[({1-[(allyloxy)carbonyl]-1H-imidazol-5-yl}methyl)amino]-2-oxoethyl}-3-chlorophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(0.11 g) was dissolved under ice cooling in a mixture solution ofdichloromethane (5.4 mL) and ion-exchange water (10.8 mL), and theretowere added dichlorobistriphenylphosphine palladium (6.7 mg, 0.005 mmol)and tri-n-butyltin hydride (0.52 mL, 1.9 mmol). The mixture was allowedto stand after vigorously stirring for 10 minutes. Thereto was addedice-cooled ion-exchanged water (10.8 mL), and the aqueous layer wasseparated and extracted with ion-exchanged water (5 mL×twice). Theaqueous solution separated and extracted was ice cooled, and thereto wasadded sodium hydrogencarbonate (16 mg, 0.19 mmol), followed by stirringfor 10 minutes. The solvent of the mixture was removed under ice coolingin vacuo over a period of 2 hours, purified with C18 reverse columnchromatography (Wakosil C18 reverse, mobile phase; ion-exchangewater/THF=100:0˜100:3) and lyophilized to give sodium(5R,6S)-3-(3-chloro-4-{2-[(1H-imidazol-5-ylmethyl)amino]-2-oxoethyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azacyclo[3.2.0]hept-2-ene-2-carboxylate(38 mg, yield 43%).

¹H NMR (400 MHz, D₂O) δ 1.15 (d, 3H, J=6.0 Hz), 2.96 (dd, 1H, J=16.8 Hz,10.0 Hz), 3.29 (dd, 1H, J=17.2 Hz, 8.4 Hz), 3.39-3.41 (m, 1H), 3.65 (s,2H), 4.10-4.28 (m, 4H), 6.91 (s, 1H), 7.18 (s, 1H), 7.18 (d, J=8.8 Hz,1H), 7.30 (d, J=8.8 Hz, 1H), 7.61 (s, 1H)

Example 74

Sodium(5R,6S)-3-(3-chloro-4-{2-[(1H-imidazol-5-ylmethyl)amino]-2-oxoethyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(76 mg) prepared by Example 73 was dissolved in dry DMF (1.5 mL), andthereto were added pivalpyloxymethyl chloride (56 μL) and benzyldiethylammonium chloride (87.6 mg). The mixture was stirred at 35° C.for 2 hours. To the reaction solution were added ethyl acetate,saturated sodium hydrogencarbonate solution and ice, and the mixture wasseparated by a separatory funnel, and the organic layer was washed withcooled water (twice), and cooled brine, dried over anhydrous sodiumsulfate and the solvent was removed in vacuo. The residue was purifiedwith silica gel column chromatography(chloroform:methanol=100:10˜100:16) to give[(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-3-(3-chloro-4-{2-[(1H-imidazol-5-ylmethyl)amino]-2-oxoethyl}phenyl)-6-[(1R)-1-hydroxyethyl]]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(30 mg, yield 49%).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (s, 9H), 1.38 (d, 3H, J=6.4 Hz),3.10-3.28 (m, 3H), 3.70 (s, 1H), 4.17-4.51 (m, 4H), 5.66 (d, 1H, J=5.6Hz), 5.79 (d, 1H, J=5.6 Hz), 6.90 (s, 1H), 7.16 (dd, J=8.0, 2.0 Hz, 1H),7.24 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.54 (s, 1H)

Test

Oral Absorption Test

A compound of Example 1 of the present invention and a pivaloyloxymethylester derivative of the compound 32, carbapenem in whichpara-hydroxyphenyl group is directly substituted, which is described inthe Journal of Medicinal Chemistry, Vol. 30, p 871-880, 1987 (which isone of the prior arts which are most relevant to the present invention)were orally administered to mice or rats. The concentration of theactive substance in serum was measured by bioassay, and absolutebioavailability was compared respectively.

Test Compound (Ester Compound) and Active Substance

The compound of Example 1 of the present invention:

[(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

The comparative compound (a pivaloyloxymethyl ester derivative ofcompound 32 described in the Journal of Medicinal Chemistry, Vol. 30, p871-880, 1987)):

[(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

An active substance of the compound of Example 1 of the presentinvention (sodium carboxylate corresponding to the compound of Example1):

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

An active substance of the comparative compound (sodium carboxylatecorresponding to the compound 32 described in the Journal of MedicinalChemistry, Vol. 30, p 871-880, 1987):

Sodium(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

(2) Oral Absorption Test in Mice

The test sample was homogonously suspended in a mixture of DMSO (5%) andmethylcellulose (0.5%). Male mice (ICR, 4 weeks old) were fed only withglucose (40%)-casamino acid (5%) solution for 20 hours, and imipenemcilastatin (2 mg) was hypodermally administered 5 minutes beforeadministration of the test sample. To thus treated mice was orallyadministered the test sample (10 mg value/kg (calculated into activesubstance). After administration of the test sample, at 5, 15, 30, and60 minutes, the blood was collected from the mice (n=3), respectively.Serum was obtained by centrifugation of the collected blood. Theconcentration of the active substance in the serum was measured bybioassay using Bacillus subtilis ATCC 6633 as an indicator. On the otherhand, the active substance (10 mg value/kg) was dissolved inphysiological saline containing 5mM MOPS and administered in a tail veinof mice, and the blood was collected as well and the serum was subjectedto bioassay.

(3) Oral Absorption in Rats

The test sample was prepared in the same manner as in the oralabsorption test in mice. Male rats (SD, 7 weeks old) were fed only withsterilized water for 20 hours, and imipenam cilastatin (2 mg) washypodermally administered 5 minutes before administration of the testsample. To thus treated rats were orally administered the test sample(10 mg value/kg (calculated into active substance)). Afteradministration of the test sample, at 5, 15, 30, and 60 minutes, theblood was collected from the rats (n=3), respectively. The concentrationof the active substance in the serum was measured by bioassay in thesame manner as in the oral absorption in mice. On the other hand, theactive substance (10 mg value/kg) was dissolved in physiological salinecontaining 5 mM MOPS and administered in a tail vein of rats, and theblood was collected as well and the serum was subjected to bioassay.

(4) Calculation of Bioavailability

In regard to the test sample, the value of the concentration of theactive substance in serum was plotted to the hours after administration,and calculated the concentration of the active substance-area underhours curve (AUC) or calculated reducing area under hours curve (AUC)from the concentration of the active substance. On the other hand, AUCwhen the active substance was intravenously administered was calculatedas mentioned above.

BA (%)=(AUC in Oral Administration/AUC in Intravenous Administration)×100

The absolute availability (BA) was calculated based on the aboveformula.

In the above tests, the comparative compound did not show oralabsorbability in the oral absorption test in rats. On the other hand,the compound of Example 1 of the present invention showedbioavailability more than 30% in both oral absorption tests in rats andmice and the maximum serum concentration (Cmax) was high.

INDUSTRIAL APPLICABILITY

By the present invention, it becomes possible to provide a β-lactamantibiotic with a high oral absorbability showing an excellentantibacterial activity over a broad range of Gram-positive andGram-negative bacteria, in particular, penicillin-resistantStreptococcus pneumoniae (PRSP) which has been isolated at an elevatedfrequency in recent years and thus causes a serious clinical problem,and Haemophilus influenzae which has acquired resistance against theexisting β-lactam antibiotics over a wide scope due topenicillin-binding protein (PBP) mutations such as β-lactamasenon-producing ampicillin-registant (BLNAR) Haemophilus influenzae.

1. A carbapenem compound represented by the following formula [1],

wherein R¹ is C₁-C₃ alkyl substituted by hydroxy, R is hydrogen atom,C₁-C₆ alkyl, C₂-C₁₂ alkoxyalkyl, phthalidyl, 2-(4-morpholinyl)ethyl,(2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-t-butyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl,or a group of the formula [4]:

wherein R⁶ is hydrogen atom or C₁-C₆ alkyl, R⁷ is C₁-C₁₀ alkyl or C₃-C₁₀cycloalky, and n is an integer of 0 or 1, and G is a group representedby the formula G3:

wherein A is —(CH₂)_(s)—NR^(a)—(CH₂)_(t)-(in which, s and t areindependently an integer of 0, and R^(a) is hydrogen atom), R⁰ ishydrogen atom, and Y² is C₁-C₄ alkyl, or a pharmaceutically acceptablesalt thereof.
 2. The carbapenem compound claimed in claim 1 or apharmaceutically acceptable salt thereof wherein R is a group of theformula [4]:

wherein R⁶ is hydrogen atom or C₁-C₆ alkyl, R⁷ is C₁-C10 alkyl or C₃-C₁₀cycloalky, and n is an integer of 0 or
 1. 3. The carbapenem compoundclaimed in claim 1 or a pharmaceutically acceptable salt thereof whereinR¹ is 1-hydroxyethyl.
 4. The carbapenem compound claimed in claim 1 or apharmaceutically acceptable salt thereof wherein R is pivaloyloxymethyl,acetyloxymethyl, acetyloxy-1-ethyl, isopropyloxycarbonyloxy-1-ethyl orcyclohexyloxycarbonyloxy-1-ethyl.
 5. The carbapenem compound claimed inclaim 1 or a pharmaceutically acceptable salt thereof wherein R ispivaloyloxymethyl.
 6. The carbapenem compound claimed in claim 1 or apharmaceutically acceptable salt thereof wherein R is phthalidyl or(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.
 7. The carbapenem compoundclaimed in claim 1 or a pharmaceutically acceptable salt thereof whereinR is hydrogen atom.
 8. A medicament containing a carbapenem compoundclaimed in claim 1 or a pharmaceutically acceptable salt thereof as anactive ingredient.
 9. An antibacterial agent containing a carbapenemcompound claimed in claim 1 or a pharmaceutically acceptable saltthereof as an active ingredient.
 10. An oral medicament containing acarbapenem compound claimed in claim 1 or a pharmaceutically acceptablesalt thereof as an active ingredient.
 11. An oral antibacterial agentcontaining a carbapenem compound claimed in claim 1 or apharmaceutically acceptable salt thereof as an active ingredient. 12.The carbapenem compound claimed in claim 1 or a pharmaceuticallyacceptable salt thereof wherein Y² is methyl.
 13. The carbapenemcompound claimed in claim 1 or a pharmaceutically acceptable saltthereof wherein R¹ is 1-hydroxyethyl, R is hydrogen atom,pivaloyloxymethyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, A is —NH—,R⁰ is hydrogen atom and Y² is methyl.
 14. The carbapenem compoundclaimed in claim 1 or a pharmaceutically acceptable salt thereof whereinR¹ is 1-hydroxyethyl, R is hydrogen atom, pivaloyloxymethyl or(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, A is —NH—, R⁰ is hydrogen atomand Y² is methyl, and said -A-R⁰— is bound to the benzene ring at metaposition and said Y² is bound to the benzene ring at para positionagainst the position where 7-oxo-1-azabicyclo[3.2.0]hept-2-ene is boundto the benzene ring.
 15. The carbapenem compound claimed in claim 1 or apharmaceutically acceptable salt thereof represented by the followingformula

wherein R and Y² are the same as defined in claim 1.